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Principles and Practice of

PEDIATRIC
INFECTIOUS DISEASES
SIXTH EDITION

EDITOR
SARAH S. LONG, md
Professor of Pediatrics
Drexel University College of Medicine
Chief Emeritus, Section of Infectious Diseases
St. Christopher’s Hospital for Children
Philadelphia, Pennsylvania

ASSOCIATE EDITORS
CHARLES G. PROBER, md
Professor of Pediatrics, Microbiology, and Immunology
Founding Executive Director, Stanford Center for Health Education
Senior Associate Vice Provost for Health Education
Stanford University School of Medicine
Stanford, California

MARC FISCHER, md, mph

Medical Epidemiologist
Arctic Investigations Program
Centers for Disease Control and Prevention
Anchorage, Alaska

DAVID W. KIMBERLIN, md
Professor and Vice Chair for Clinical and Translational Research
Co-Director, Division of Pediatric Infectious Diseases
Department of Pediatrics
University of Alabama at Birmingham Heersink School of Medicine
and the Children’s Hospital of Alabama
Birmingham, Alabama
Elsevier
1600 John F. Kennedy Blvd.
Ste 1600
Philadelphia, PA 19103-2899

PRINCIPLES AND PRACTICE OF PEDIATRIC INFECTIOUS DISEASES, ISBN-13: 978-0-323-75608-2

SIXTH EDITION
Copyright © 2023 by Elsevier, Inc. All rights reserved.

Previous editions copyrighted 2018, 2012, 2008, 2003, 1997 by Elsevier, Inc.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
permission in writing from the publisher. Details on how to seek permission, further information about the
Publisher’s permissions policies, and our arrangements with organizations such as the Copyright Clearance
Center and the Copyright Licensing Agency can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).

All chapters published herein that are authored or co-authored by an employee of the US government are in
the public domain. In addition, the following chapters are in the public domain:
Chapter 113: Management of HIV Infection
Chapter 218: Flaviviruses
Chapter 278: Diphyllobothriidae, Dipylidium and Hymenolepis Species
Chapter 285: Blood Trematodes: Schistosomiasis

Notice

Practitioners and researchers must always rely on their own experience and knowledge in evaluating
and using any information, methods, compounds, or experiments described herein. Because of rapid
advances in the medical sciences in particular, independent verification of diagnoses and drug dosages
should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors,
or contributors for any injury and/or damage to persons or property as a matter of products liability,
negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas
contained in the material herein.

ISBN-13: 978-0-323-75608-2

Publisher: Sarah Barth

Senior Content Development Specialist: Ann Anderson
Publishing Services Manager: Catherine Albright Jackson
Senior Project Manager: Doug Turner
Designer: Bridget Hoette

Printed in India

Last digit is the print number: 9 8 7 6 5 4 3 2 1

 Preface
The field of infectious diseases is ever changing with emerging pathogens, Part II. Clinical Syndromes and Cardinal Features of Infectious Dis-
globalization of people and microbes, escalating antimicrobial resistance, eases: Approach to Diagnosis and Initial Management: new content on
increasing cohorts of children living with immunocompromising con- conditions that mimic infectious diseases (such as hemophagocytic lym-
ditions, novel diagnostic methods, expanding therapeutic options, and phohistiocytosis, macrophage activation syndrome, and SARS-CoV-2
continuous development of vaccines and strategies for implementation. related conditions and vaccine adverse events); developmental stages of
As the conditions on the ground become increasingly complex, so do the innate and adaptive immunity; recognition and management of infec-
roles of infectious diseases experts. On a micro-level, we are entrusted tions and risks due to congenital and acquired immunocompromising
to plan the approach to an individual patient with a potentially previ- conditions; expanded chapters on infections related to receipt of biologic
ously undescribed infection, while on a macro-level we are challenged response modifier therapy and corticosteroids; expanded content on cen-
to expand the field’s knowledge, educate others, and steward the public’s tral nervous system infectious and parainfectious conditions; a new chap-
health. ter on maternal chorioamnionitis and its perinatal impact; new morbidi-
ties and evidence-based approaches to preventing healthcare-associated
Our goal is to provide a comprehensive, reliable, up-to-date reference infections.
focused on evidence-based, practical information that is required to care
for neonates, infants, children, and adolescents with any infectious dis- Part III. Etiologic Agents of Infectious Diseases: significant new entries
ease. We aim to guide the clinician to understand the problem, diagnose related to molecular and metagenomic diagnostics, antimicrobial resis-
the etiology, and effectively manage the patient to optimize outcome. Our tance, and therapies for bacterial infections, especially infections due to
scope also includes strategies for prevention and control of infectious dis- staphylococci, pneumococci, gonococci, mycobacteria, and gram-nega-
eases and for antimicrobial stewardship that will aid in the management tive bacilli; SARS-CoV-2 and Zika viruses, new antiviral therapies, new
of individual patients and will provide a basis for policy development for vaccines, and some under development; evidence and guidance where
institutions. Features permeating the sixth edition include direct links to evidence is incomplete for use and monitoring of agents to treat fungal
the referenced primary medical literature in your eBook and addresses infections; comprehensive and latest guidance for management of proto-
for web-based resources, such as to access updates of guidelines, to obtain zoal infections, including toxoplasmosis, malaria, and other pathogens
a restricted therapeutic agent, or to access an expert to aid in manage- of immigrants.
ment of a rare disease. We have substantially expanded the use of tables,
figures, image-illustrated cases, scan- and slide-ready graphics and algo- Part IV. Laboratory Diagnosis and Therapy of Infectious Diseases:
rithms, and Key Points boxes to optimize rapid visual access to important through the burgeoning world of molecular diagnostics, the best tests for
information. laboratory identification of infectious agents; differentiating features of
commonly used laboratory tests to measure the inflammatory response
We have engaged subject-specific experts to author all chapters and have and predict the cause; new insights into principles of use of anti-infective
imposed a prescribed, predictable, and focused format that will reliably therapies; expanded primer on the pharmacodynamic basis of optimal
reward the reader with answers to the question, what should I do next? use of antimicrobial agents; mechanisms and best laboratory techniques to
With a substantial number of authors from the Centers for Disease Con- detect newly emerging antimicrobial resistance; new antimicrobial agents
trol and Prevention, the American Academy of Pediatrics’ Committee on for treating bacterial, fungal, viral, and parasitic infections.
Infectious Diseases and the Section on Infectious Diseases, the Pediatric
Infectious Diseases Society, and infection prevention advisory groups, The primary audience for our textbook is the subspecialist in infectious
we have attempted to present consistent recommendations and to build a diseases who provides care for or advises on policy regarding infants,
compendium of best practices. Examples of new content are highlighted children, and adolescents. We hope that our book also serves as a daily
here, within the context of the four major sections of the book. “consultant” for pediatricians and family physicians and a valuable
resource for surgeons, clinical microbiologists, experts in infection con-
Part I. Understanding, Controlling, and Preventing Infectious Diseas- trol, health policy makers, and other health professionals who care for
es: a primer in biostatistics; expanded use of immunoglobulin products; and about children.
latest vaccine recommendations and schedules for immunizations for
healthy and special hosts, and adverse event–reporting systems; listings
of resources in electronic, telephone, and paper media; up-to-date recom- Sarah S. Long
mendations for infection prevention and control for hospitals and offices; Charles G. Prober
special considerations for children who are in out-of-home care, are ex- Marc Fischer
posed to pets and exotic animals, or who are traveling or immigrating. David W. Kimberlin

v
 Acknowledgments
With special contributions of clinical images by James H. Brien, DO,
Adjunct Professor of Pediatrics, Infectious Diseases, Texas A&M University College of Medicine, McLane Children’s Hospital, Baylor Scott & White
Health, Temple, Texas

vi
 With our spouses (Bob, Laura, Lisa, and Kim)
our children (Stephen, Suzanne, and Caroline; Meghan and Andrew;
Sydney and Madison; Will, Claire, and Katherine)
and other loved ones
whose patience and endurance are our bedrock,

We share the achievement of this book.

To our mentors and colleagues, who share

knowledge and stimulate learning,

We give credit for the book’s value.

To those who practice medicine as an art based on science,

and for the children whom they will serve,
We offer the book’s lessons.

To Anthony S. (Tony) Fauci

who has been true north through all of the challenges and advances
that we have experienced for the past two years,
and to our other colleagues who have tirelessly and selflessly advanced the science,
public health, education, training, and frontline patient care throughout the most
historic infectious disease challenge of our lifetime,

We dedicate the sixth edition.

vii
 Contributors
Mark J. Abzug, MD Upton D. Allen, Jr., MBBS, MSc Shai Ashkenazi, MD, MSc
Professor of Pediatrics–Infectious Diseases, Professor of Paediatrics, University of Toronto Professor and Dean, Adelson School of
University of Colorado School of Medicine; Faculty of Medicine; Division of Infectious Medicine, Ariel University, Department of
Division of Infectious Diseases, Children’s Diseases, Hospital for Sick Children, Toronto, Pediatrics A, Schneider Children’s Medical
Hospital Colorado, Aurora, Colorado Ontario, Canada Center, Petach Tikva, Israel
Introduction to Picornaviridae; Enteroviruses Adenoviruses Plesiomonas shigelloides; Shigella Species
and Parechoviruses
Gerardo Alvarez-Hernández, MD, PhD, MPH Liat Ashkenazi-Hoffnung, MD
Elisabeth E. Adderson, MD, MSc Professor of Medicine and Health Sciences, Sackler Faculty of Medicine, Tel-Aviv
Associate Professor of Pediatrics, University of Universidad de Sonora, Hermosillo, Mexico University, Tel-Aviv, Israel; Head, Day
Tennessee Health Sciences Center; Associate Rickettsia rickettsii (Rocky Mountain Spotted Hospitalization Department, Attending
Member, Department of Infectious Diseases, Fever) Physician, Pediatric Infectious Diseases Unit,
St. Jude Children’s Research Hospital and St. Schneider Children’s Medical Center, Petach-
Jude Graduate School of Biomedical Sciences, Krow Ampofo, MBChB Tikva, Israel
Memphis, Tennessee Professor of Pediatrics, University of Utah Plesiomonas shigelloides
Infectious Complications of Antibody School of Medicine; Attending Physician,
Deficiency Infectious Diseases, Primary Children’s Edwin J. Asturias, MD
Hospital, Salt Lake City, Utah Professor of Pediatrics, University of Colorado
Aastha Agarwal, MD Streptococcus pneumoniae School of Medicine; Professor of Epidemiology,
Senior Resident, Dermatology, Dr RML Associate Director, Center for Global Health,
Hospital, ABVIMS, Delhi, India Evan J. Anderson, MD Colorado School of Public Health; Jules Amer
Superficial Fungal Infections Professor of Pediatrics and Medicine, Emory Chair, Department of Community Pediatrics,
University School of Medicine; Division of Children’s Hospital Colorado, Aurora,
Allison L. Agwu, MD, ScM Infectious Diseases, Children’s Healthcare of Colorado
Professor of Pediatrics, Johns Hopkins School Atlanta, Atlanta, Georgia Escherichia coli
of Medicine, Baltimore, Maryland Campylobacter jejuni and Campylobacter coli;
Infectious Complications of HIV Infection Other Campylobacter Species Kestutis Aukstuolis, DO
Division of Allergy and Infectious Diseases,
Lindsey Albenberg, DO Grace D. Appiah, MD, MS Department of Medicine, University of
Assistant Professor of Pediatrics, University Medical Epidemiologist, Waterborne Disease Washington, Seattle, Washington
of Pennsylvania Perelman School of Prevention Branch, Centers for Disease Control Immunologic Development and Susceptibility
Medicine; Attending Physician, Division of and Prevention, Atlanta, Georgia to Infection
Gastroenterology, Hepatology, and Nutrition, Vibrio cholerae (Cholera)
Children’s Hospital of Philadelphia, Philadelphia, Vahe Badalyan, MD, MPH, MBA
Pennsylvania Monica I. Ardura, DO, MSCS Attending Physician, Department of
Anaerobic Bacteria: Clinical Concepts and the Associate Professor of Pediatrics, The Ohio Gastroenterology, Hepatology, and Nutrition,
Microbiome in Health and Disease State University College of Medicine; Medical Children’s National Hospital, Washington,
Director, Host Defense Program, Division of District of Columbia
Jonathan Albert, MD Infectious Diseases, Nationwide Children’s Acute Hepatitis
Fellow, Division of Infectious Diseases, Hospital, Columbus, Ohio
Children’s National Hospital, Washington, Risk Factors and Infectious Agents in Children Carol J. Baker, MD
District of Columbia With Cancer: Fever and Granulocytopenia; Professor of Pediatrics–Infectious Diseases,
Peritonitis Clinical Syndromes of Infection in Children McGovern Medical School, University of Texas
With Cancer; Citrobacter Species Health Science Center, Houston, Texas
Kevin Alby, PhD, D(ABMM) Bacterial Infections in the Neonate;
Assistant Professor of Pathology and Stephen S. Arnon, MD, MPH Streptococcus agalactiae (Group B
Laboratory Medicine, University of North Founder and Chief, Infant Botulism Treatment Streptococcus)
Carolina School of Medicine; Director, and Prevention Program, California
Bacteriology and Susceptibility Testing, UNC Department of Public Health, Richmond, Karthik Balakrishnan, MD, MPH
Medical Center, Chapel Hill, North Carolina California Associate Professor of Otolaryngology,
Mechanisms and Detection of Antimicrobial Clostridium botulinum (Botulism) Stanford University School of Medicine,
Resistance Lucile Packard Children’s Hospital, Stanford,
Naomi E. Aronson, MD California
Grace M. Aldrovandi, MD, CM Professor of Medicine, Director, Infectious Otitis Externa and Necrotizing Otitis Externa
Professor of Pediatrics, David Geffen School Diseases Division, Uniformed Services
of Medicine at UCLA; Chief, Division of University of the Health Sciences, Bethesda, Elizabeth D. Barnett, MD
Infectious Diseases, UCLA Mattel Children’s Maryland Professor of Pediatrics, Boston University
Hospital, Los Angeles, California Leishmania Species (Leishmaniasis) School of Medicine; Attending Physician,
Immunopathogenesis of HIV-1 Infection Department of Pediatrics, Boston Medical
Ann M. Arvin, MD Center, Boston, Massachusetts
Lucile Salter Packard Professor of Pediatrics, Infectious Diseases in Refugee and
Professor of Microbiology and Immunology, Internationally Adopted Children; Protection
Stanford University School of Medicine, of Travelers
Stanford, California
Varicella-Zoster Virus

viii
 Contributors

Kirsten Bechtel, MD Thomas G. Boyce, MD, MPH Connie F. Cañete-Gibas, PhD

Professor of Pediatrics, Yale School of Associate Professor of Pediatrics, Infectious Clinical Mycologist, Department of Pathology
Medicine; Attending Physician, Pediatric Diseases and Immunology, Levine Children’s and Laboratory Medicine, Fungus Testing
Emergency Medicine, Yale-New Haven Hospital, Charlotte, North Carolina Laboratory, UT Health San Antonio, San
Children’s Hospital, New Haven, Connecticut Otitis Externa and Necrotizing Otitis Externa Antonio, Texas
Infectious Diseases Associated With Child Classification of Fungi; Agents of
Abuse John S. Bradley, MD Hyalohyphomycosis and Phaeohyphomycosis;
Professor of Pediatrics, University of California Agents of Mucormycosis; Malassezia Species;
William E. Benitz, MD San Diego School of Medicine; Director, Sporothrix schenckii Complex (Sporotrichosis)
Philip Sunshine Professor in Neonatology Infectious Diseases, Rady Children’s Hospital
Emeritus, Division of Neonatal and San Diego, San Diego, California Joseph B. Cantey, MD, MPH
Developmental Medicine, Stanford University Antimicrobial Chemoprophylaxis; Principles Associate Professor of Pediatrics, Joe R. &
School of Medicine, Palo Alto, California of Anti-Infective Therapy; Pharmacokinetic Teresa Lozano Long School of Medicine;
Clinical Approach to the Neonate With and Pharmacodynamic Basis of Optimal Division of Neonatal-Perinatal Medicine,
Suspected Infection; Chorioamnionitis and Antimicrobial Therapy; Antibacterial Agents Division of Immunology and Infectious
Neonatal Consequences Diseases, University of Texas Health San
Denise F. Bratcher, DO Antonio, San Antonio, Texas
Rachel Berkovich, MD Professor of Pediatrics, University of Missouri Pediatric Healthcare: Infection Epidemiology,
Clinical Assistant Professor, University of at Kansas City School of Medicine; Attending Prevention and Control, and Antimicrobial
Missouri at Kansas City School of Medicine; Physician, Division of Infectious Diseases, Stewardship; Healthcare-Associated Infections
Medical Director of Imaging, Department Children’s Mercy–Kansas City, Kansas City, in the Neonate
of Radiology, Cardinal Glennon Children’s Missouri
Hospital, St. Louis, Missouri; Vice Chair, Arcanobacterium haemolyticum; Bacillus Species Paul Cantey, MD, MPH
Department of Radiology, Children’s Mercy– (Including Anthrax); Other Corynebacteria; Chief, Parasitic Diseases Branch, Centers for
Kansas City, Kansas City, Missouri Other Gram-Positive Bacilli Disease Control and Prevention, Atlanta,
Focal Suppurative Infections of the Nervous Georgia
System Paula K. Braverman, MD Blood and Tissue Nematodes: Filarial Worms;
Professor of Pediatrics, University of Echinococcus Species: Agents of Echinococcosis
David M. Berman, DO, MS Massachusetts Medical School–Baystate;
Assistant Professor of Pediatric–Infectious Chief, Adolescent Medicine, Department Cristina V. Cardemil, MD, MPH
Diseases, Johns Hopkins School of Medicine; of Pediatrics, Baystate Children’s Hospital, Medical Epidemiologist, Division of Viral
Johns Hopkins All Children’s Hospital, St Springfield, Massachusetts Diseases, Centers for Disease Control and
Petersburg, Florida Urethritis, Vulvovaginitis, and Cervicitis Prevention, Atlanta, Georgia
Infections in Hematopoietic Cell Transplant Caliciviruses; Astroviruses
Recipients Itzhak Brook, MD
Professor of Pediatrics, Georgetown University Mary T. Caserta, MD
Stephanie R. Bialek, MD, MPH School of Medicine, Washington, District of Professor of Pediatrics, University of Rochester
Chief, Parasitic Diseases Branch, Division of Columbia School of Medicine and Dentistry; Division
Parasitic Diseases and Malaria, Centers for Anaerobic Bacteria: Clinical Concepts and the of Infectious Diseases, Golisano Children’s
Disease Control and Prevention, Atlanta, Microbiome in Health and Disease; Clostridium Hospital, University of Rochester Medical
Georgia tetani (Tetanus); Other Clostridium Species; Center, Rochester, New York
Intestinal Trematodes Bacteroides and Prevotella Species and Other Human Herpesvirus 6 and 7 (Roseola,
Anaerobic Gram-Negative Bacilli Exanthem Subitum); Human Herpesvirus 8
Else M. Bijker, MD, PhD (Kaposi Sarcoma-Associated Herpesvirus)
Postdoctoral Researcher, Oxford Vaccine Kevin Edward Brown, MD, MRCP
Group; Paediatrician, Department of Consultant Medical Virologist, Immunisation Luis A. Castagnini, MD, MPH
Paediatrics, University of Oxford, Oxford, and Vaccine Preventable Diseases, UK Health Director, Vaccine Clinical Research, Merck &
United Kingdom Security Agency, London, United Kingdom Co., North Wales, Pennsylvania
Neisseria meningitidis Human Parvoviruses (Parvovirus B19 and Helicobacter pylori
Bocavirus)
Matthew J. Bizzarro, MD Jessica R. Cataldi, MD, MSCS
Professor of Pediatrics, Yale University School Kristina P. Bryant, MD Assistant Professor of Pediatrics, University
of Medicine; Medical Director, Yale Neonatal Professor of Pediatrics–Infectious Diseases, of Colorado School of Medicine; Section
Intensive Care Network, Yale–New Haven University of Louisville School of Medicine; of Infectious Diseases, Children’s Hospital
Children’s Hospital, New Haven, Connecticut Epidemiologist, Norton Children’s Hospital, Colorado, Aurora, Colorado
Healthcare-Associated Infections in the Louisville, Kentucky Moraxella Species
Neonate Tickborne Infections
Ellen Gould Chadwick, MD
Karen C. Bloch, MD, MPH Andres F. Camacho-Gonzalez, MD, MSc Professor of Pediatrics, Northwestern
Professor of Medicine and Infectious Diseases, Associate Professor of Pediatrics, Emory University Feinberg School of Medicine;
Vanderbilt University Medical Center, University School of Medicine; Division of Susan B. DePree Founders’ Board Professor
Nashville, Tennessee Pediatric Infectious Diseases, Children’s in Pediatric Adolescent and Maternal HIV
Encephalitis Healthcare of Atlanta, Atlanta, Georgia Infection, Director, Section of Pediatric,
Trypanosoma Species (Trypanosomiasis) Adolescent and Maternal HIV Infection, Ann
Joseph A. Bocchini, Jr., MD & Robert H. Lurie Children’s Hospital of
Professor and Vice Chairman, Department Chicago, Chicago, Illinois
of Pediatrics, Tulane University School of Nocardia Species
Medicine, New Orleans, Louisiana; Director,
Willis-Knighton Children’s Health Services,
Willis-Knighton Health System, Shreveport,
Louisiana
Infections Related to Pets and Exotic Animals

ix
 Contributors

Rebecca J. Chancey, MD C. Buddy Creech, MD, MPH H. Dele Davies, MD, MHCM
Medical Officer, Parasitic Diseases Branch, Professor in Pediatrics, Director, Vanderbilt Professor of Pediatrics and Public Health,
Center for Global Health, Centers for Disease Vaccine Research Program, Edie Carell University of Nebraska Medical Center,
Control and Prevention, Atlanta, Georgia Johnson Chair, Division of Pediatric Infectious Omaha, Nebraska
Clonorchis, Opisthorchis, Fascioloa, and Diseases, Vanderbilt University School of Infections Related to Biologic Response
Paragonimus Species; Antiparasitic Agents Medicine and Medical Center, Nashville, Modifying Drug Therapy; Infectious
Tennessee Complications of Corticosteroid Therapy
Cara C. Cherry, DVM, MPH, DACVPM Musculoskeletal Symptom Complexes;
Veterinary Epidemiologist, Rickettsial Myositis, Pyomyositis, and Necrotizing Fatimah S. Dawood, MD
Zoonoses Branch, Centers for Disease Control Fasciitis; Transient Synovitis; Staphylococcus Medical Officer, Influenza Division, Centers
and Prevention, Atlanta, Georgia aureus for Disease Control and Prevention, Atlanta,
Coxiella burnetii (Q fever) Georgia
Jonathan D. Crews, MD, MS Influenza Viruses
Silvia S. Chiang, MD Assistant Professor of Pediatric–Infectious
Assistant Professor of Pediatrics, Warren Alpert Diseases, Baylor College of Medicine/ J. Christopher Day, MD
Medical School of Brown University; Attending Children’s Hospital of San Antonio, San Assistant Professor of Pediatrics, University of
Physician, Infectious Diseases, Hasbro Antonio, Texas Missouri at Kansas City; Attending Physician,
Children’s Hospital, Providence, Rhode Island Other Gastric and Enterohepatic Helicobacter Division of Infectious Diseases, Children’s
Mycobacterium tuberculosis Species Mercy–Kansas City, Kansas City, Missouri
Lymphatic System and Generalized
Mary Choi, MD, MPH Donna Curtis, MD, MPH Lymphadenopathy; Mediastinal and Hilar
Medical Officer, Viral Special Pathogens Associate Professor of Pediatrics, University Lymphadenopathy
Branch, Centers for Disease Control and of Colorado School of Medicine; Section
Prevention, Atlanta, Georgia of Infectious Diseases, Children’s Hospital M. Teresa de la Morena, MD
Bunyaviruses; Filoviruses and Arenaviruses Colorado, Aurora, Colorado Professor of Pediatrics, University of
Pneumonia in the Immunocompromised Host Washington School of Medicine; Division
John C. Christenson, MD of Immunology, Seattle Children’s Hospital,
Professor of Clinical Pediatrics, Ryan White Nigel Curtis, DCH, DTM&H, MRCP, Seattle, Washington
Center for Pediatric Infectious Diseases and MRCPCH, PhD Immunologic Development and Susceptibility
Global Health, Indiana University School Professor of Paediatrics, The University of to Infection
of Medicine; Riley Hospital for Children, Melbourne; Head of Infectious Diseases,
Indianapolis, Indiana The Royal Children’s Hospital Melbourne, Gregory P. DeMuri, MD
Histoplasma capsulatum (Histoplasmosis); Leader of Infectious Diseases Group, Murdoch Professor of Pediatrics, University of Wisconsin
Laboratory Diagnosis of Infection Due to Children’s Research Institute, Parkville, School of Medicine and Public Health; Division
Bacteria, Fungi, Parasites, and Rickettsiae Victoria, Australia of Infectious Diseases, American Family
Infections Related to the Upper and Middle Children’s Hospital, Madison, Wisconsin
Susan E. Coffin, MD, MPH Airways; Mycobacterium Nontuberculosis Sinusitis; Preseptal and Orbital Infections
Professor of Pediatrics, Perelman School of Species
Medicine at the University of Pennsylvania; Dickson D. Despommier, PhD
Division of Infectious Diseases, Children’s Lara A. Danziger-Isakov, MD, MPH Emeritus Professor of Microbiology and
Hospital of Philadelphia, Philadelphia, Professor of Pediatrics, University of Immunology, Columbia University College of
Pennsylvania Cincinnati College of Medicine; Division of Physicians and Surgeons, New York, New York
Healthcare-Associated Infections Infectious Diseases, Cincinnati Children’s Tissue Nematodes
Hospital Medical Center, Cincinnati, Ohio
Amanda Cohn, MD Infectious Complications in Special Hosts Daniel S. Dodson, MS, MD
Chief Medical Officer, National Center for Assistant Professor of Pediatrics, University of
Immunization and Respiratory Diseases, Toni Darville, MD California Davis School of Medicine; Division
Centers for Disease Control and Prevention, Professor of Pediatrics, University of North of Pediatric Infectious Diseases, UC Davis
Atlanta, Georgia Carolina at Chapel Hill; Chief, Infectious Health, Sacramento, California
Neisseria meningitidis Diseases, Department of Pediatrics, North Escherichia coli
Carolina Children’s Hospital, Chapel Hill,
Despina G. Contopoulos-Ioannidis, MD North Carolina Stephen J. Dolgner, MD
Clinical Associate Professor of Pediatrics, Chlamydia trachomatis Assistant Professor of Pediatrics, Baylor College
Division of Infectious Diseases, Stanford of Medicine; Division of Cardiology, Texas
University School of Medicine, Stanford, Gregory A. Dasch, PhD Children’s Hospital, Houston, Texas
California Biotechnology Applications Laboratory Endocarditis and Other Intravascular
Toxoplasma gondii (Toxoplasmosis) Director, Rickettsial Zoonoses Branch, Centers Infections
for Disease Control and Prevention, Atlanta,
James H. Conway, MD Georgia Clinton Dunn, MD
Professor of Pediatrics, University of Wisconsin Other Rickettsia Species Department of Medicine, Division of Allergy
School of Medicine & Public Health; Associate and Infectious Diseases, University of
Director, Global Health Institute, University of Irini Daskalaki, MD Washington, Seattle, Washington
Wisconsin–Madison, Madison, Wisconsin Global and Community Health Physician Immunologic Development and Susceptibility
Mastoiditis Coordinator, Princeton University Health to Infection
Services, Princeton, New Jersey
Margaret M. Cortese, MD Corynebacterium diphtheriae; Leptospira Jonathan Dyal, MD, MPH
Captain, United States Public Health Service, Species (Leptospirosis); Other Borrelia Species Epidemic Intelligence Service Officer, Viral
Division of Viral Diseases, National Center and Spirillum minus Special Pathogens Branch, Centers for Disease
for Immunization and Respiratory Diseases, Control and Prevention, Atlanta, Georgia
Centers for Disease Control and Prevention, Filoviruses and Arenaviruses
Atlanta, Georgia
Rotaviruses

x
 Contributors

Kathryn M. Edwards, MD Guliz Erdem, MD Randall G. Fisher, MD

Professor of Pediatrics, Sarah H. Sell and Professor of Pediatrics, Ohio State University Professor of Pediatrics, Eastern Virginia
Cornelius Vanderbilt Chair, Department of College of Medicine; Section of Infectious Medical School; Medical Director, Division
Pediatrics, Vanderbilt University School of Diseases, Nationwide Children’s Hospital, of Pediatric Infectious Diseases, Children’s
Medicine, Nashville, Tennessee Columbus, Ohio Hospital of The King’s Daughters, Norfolk,
Prolonged, Recurrent, and Periodic Fever Acinetobacter Species; Less Commonly Virginia
Syndromes; Bordetella pertussis (Pertussis) and Encountered Nonenteric Gram-Negative Evaluation of the Child With Suspected
Other Bordetella Species Bacilli; Eikenella, Pasteurella, and Immunodeficiency; Infectious Complications
Chromobacterium Species of Dysfunction or Deficiency of
Morven S. Edwards, MD Polymorphonuclear and Mononuclear
Professor of Pediatrics, Baylor College of Marina E. Eremeeva, MD, PhD, ScD Phagocytes
Medicine; Attending Physician, Section of Professor of Biostatistics, Epidemiology,
Infectious Diseases, Texas Children’s Hospital, and Environmental Health Sciences, Jiann- Patricia Michele Flynn, MD
Houston, Texas Ping Hsu College of Public Health, Georgia Professor of Pediatrics and Preventive
Bacterial Infections in the Neonate; Southern University, Statesboro, Georgia Medicine, University of Tennessee Health
Streptococcus agalactiae (Group B Other Rickettsia Species Sciences Center; Member, Department
Streptococcus) of Infectious Diseases, St. Jude Children’s
Douglas H. Esposito, MD, MPH Research Hospital, Memphis, Tennessee
Dawn Z. Eichenfield, MD, PhD Medical Epidemiologist, Office of Refugee Cryptosporidium Species; Cystoisospora
Assistant Clinical Professor of Dermatology, Resettlement, Administration for Children (Isospora) and Cyclospora Species
University of California, Rady Children’s and Families, US Department of Health and
Hospital San Diego, San Diego, California Human Services, Atlanta, Georgia Monique A. Foster, MD, MPH
Purpura Sarcocystis Species Medical Epidemiologist, Division of Viral
Hepatitis, Centers for Disease Control and
Lawrence F. Eichenfield, MD Monica M. Farley, MD Prevention, Atlanta, Georgia
Distinguished Professor of Dermatology and Jonas A. Shulman Professor of Medicine, Hepatitis C Virus; Hepatitis A Virus
Pediatrics, University of California, Rady Director, Division of Infectious Diseases,
Children’s Hospital San Diego, San Diego, Emory University School of Medicine, Atlanta, LeAnne M. Fox, MD, MPH, DTM&H
California Georgia Chief, Meningitis and Vaccine Preventable
Purpura Listeria monocytogenes Diseases Branch, Division of Parasitic Diseases
and Malaria, Center for Global Health, Centers
Dirk M. Elston, MD Anat R. Feingold, MD, MPH for Disease Control and Prevention, Atlanta,
Professor and Chair, Department of Associate Professor of Pediatrics, Cooper Georgia
Dermatology, Medical University of South Medical School of Rowan University; Intestinal Trematodes
Carolina, Charleston, South Carolina Chief, Pediatric Infectious Diseases, Cooper
Ectoparasites (Lice and Scabies) University Hospital, Camden, New Jersey †Michael M. Frank, MD
Anaerobic Cocci; Anaerobic Gram- Professor of Pediatrics and Immunology, Duke
Beth Emerson, MD Positive Nonsporulating Bacilli (Including University School of Medicine; Attending
Associate Clinical Professor of Pediatrics, Actinomycosis) Physician, Duke University Medical Center,
Yale University School of Medicine; Section Durham, North Carolina
of Pediatric Emergency Medicine, Yale–New Kristina N. Feja, MD, MPH Infectious Complications of Complement
Haven Children’s Hospital, New Haven, Clinical Associate Professor of Pediatrics, Deficiency and Diseases of Its Dysregulation
Connecticut Robert Wood Johnson Medical School,
Infectious Diseases Associated With Child Rutgers University; Chief, Division of Pediatric Douglas R. Fredrick, MD
Abuse Infectious Diseases, Saint Peter’s University Professor of Ophthalmology, Oregon Health
Hospital, New Brunswick, New Jersey & Science University; Casey Eye Institute,
Leslie A. Enane, MD, MSc Babesia Species (Babesiosis) Portland, Oregon
Assistant Professor of Pediatrics, Indiana Conjunctivitis in the Neonatal Period
University School of Medicine; Director, Adam Finn, BA (Hons), MA, BM, BCh, PhD (Ophthalmia neonatorum); Conjunctivitis
Pediatric HIV Services, Ryan White Center Professor of Paediatrics, University of Bristol; Beyond the Neonatal Period; Infective Keratitis;
for Pediatric Infectious Diseases and Global Honorary Consultant, Bristol Royal Hospital Infective Uveitis, Retinitis, and Chorioretinitis;
Health, Riley Hospital for Children at Indiana for Children, Bristol, United Kingdom Endophthalmitis
University Health, Indianapolis, Indiana Neisseria meningitidis
Agents of Eumycotic Mycetoma: Robert W. Frenck, Jr., MD
Pseudallescheria boydii and Scedosporium Marc Fischer, MD, MPH Professor of Pediatrics, University of
apiospermum Medical Epidemiologist, Arctic Investigations Cincinnati College of Medicine; Division of
Program, Centers for Disease Control and Infectious Diseases, Cincinnati Children’s
Moshe Ephros, MD Prevention, Anchorage, Alaska Hospital Medical Center, Cincinnati, Ohio
Director, Pediatric Infectious Diseases Unit, Coltivirus (Colorado Tick Fever); Flaviviruses; Giardia intestinalis (Giardiasis)
Carmel Medical Center; Associate Clinical Bunyaviruses
Professor of Pediatrics (Retired), Faculty James Gaensbauer, MD, MScPH
of Medicine, Technion-Israel Institute of Brian T. Fisher, DO, MPH, MSCE Associate Professor of Pediatrics, University
Technology, Haifa, Israel Associate Professor of Pediatrics and of Colorado School of Medicine, Center for
Leishmania Species (Leishmaniasis) Epidemiology, Perelman School of Medicine Global Health, Department of Epidemiology,
at the University of Pennsylvania; Division Colorado School of Public Health, Aurora,
of Infectious Diseases, Children’s Hospital of Colorado; Pediatric Infectious Diseases,
Philadelphia, Philadelphia, Pennsylvania Department of Pediatrics, Denver Health
Candida Species Medical Center, Denver, Colorado
Infection Related to Trauma

†Deceased.

xi
 Contributors

Hayley A. Gans, MD Amanda M. Green, MD Rana F. Hamdy, MD, MPH, MSCE

Professor of Pediatrics–Infectious Diseases, Clinical Fellow, Department of Infectious Assistant Professor of Pediatrics, George
Stanford University School of Medicine, Diseases, St Jude Children’s Research Hospital, Washington University School of Medicine and
Stanford, California Memphis, Tennessee Health Sciences; Attending Physician, Division
Hemophagocytic Lymphohistiocytosis and Infectious Complications of Antibody of Infectious Diseases, Children’s National
Macrophage Activation Syndrome Deficiency Hospital, Washington, District of Columbia
Peritonitis; Appendicitis; Intra-abdominal,
Gregory M. Gauthier, MD Michael Green, MD, MPH Visceral, and Retroperitoneal Abscesses
Associate Professor (CHS) of Medicine, Professor of Pediatrics, Surgery & Clinical
University of Wisconsin–Madison, Madison, and Translational Research, University of Jin-Young Han, MD, PhD
Wisconsin Pittsburgh School of Medicine; Medical Associate Professor of Clinical Pediatrics, Weill
Blastomyces Species (Blastomycosis) Director, Infection Prevention and Cornell Medicine; Attending Pediatrician,
Antimicrobial Stewardship, Division of Phyllis and David Komansky Children’s
Patrick Gavigan, MD Infectious Diseases, UPMC Children’s Hospital Hospital at NewYork–Presbyterian/Weill
Assistant Professor of Pediatrics, Penn State of Pittsburgh, Pittsburgh, Pennsylvania Cornell Medical Center, New York, New York
University/Hershey Medical Center; Division Infections in Solid Organ Transplant Recipients Bartonella Species (Cat-Scratch Disease)
of Infectious Diseases, Penn State Children’s
Hospital, Hershey, Pennsylvania Daniel Griffin, MD, PhD Lori K. Handy, MD
Erythematous Macules and Papules Clinical Instructor of Medicine, Division of Clinical Assistant Professor of Pediatrics,
Infectious Diseases, Columbia University Perelman School of Medicine at the University
Jeffrey S. Gerber, MD, PhD College of Physicians and Surgeons, New York, of Pennsylvania; Division of Infectious
Associate Professor of Pediatrics, Perelman New York Diseases, Children’s Hospital of Philadelphia,
School of Medicine at the University of Tissue Nematodes Philadelphia, Pennsylvania
Pennsylvania; Attending Physician, Division Healthcare-Associated Infections
of Infectious Diseases, Children’s Hospital of Patricia M. Griffin, MD
Philadelphia, Philadelphia, Pennsylvania Chief, National Surveillance Team, Division of Benjamin Hanisch, MD
Principles of Anti-Infective Therapy Foodborne, Waterborne, and Environmental Assistant Professor of Pediatrics, George
Diseases, National Center for Emerging and Washington University School of Medicine and
Yael Gernez, MD, PhD Zoonotic Infectious Diseases, Centers for Health Sciences; Attending Physician, Division
Assistant Professor of Pediatrics, Division of Disease Control and Prevention, Atlanta, of Infectious Diseases, Children’s National
Allergy, Immunology, and Rheumatology, Georgia Hospital, Washington, District of Columbia
Stanford University School of Medicine, Other Vibrio Species Infections in Solid Organ Transplant Recipients
Stanford, California
Infectious Complications of Deficiencies of David C. Griffith, MD Marvin B. Harper, MD
Cell-Mediated Immunity Other Than AIDs: Assistant Professor of Medicine and Pediatrics, Associate Professor of Pediatrics, Harvard
Primary Immunodeficiencies Johns Hopkins School of Medicine, Baltimore, Medical School; Divisions of Emergency
Maryland Medicine and Infectious Diseases, Boston
Francis Gigliotti, MD Management of HIV Infection Children’s Hospital, Boston, Massachusetts
Professor of Pediatrics, University of Rochester Infection Related to Bites
School of Medicine and Dentistry, Rochester, Piyush Gupta, MD
New York Professor and Head, Department of Pediatrics, Aaron M. Harris, MD, MPH
Pneumocystis jirovecii University College of Medical Sciences, Delhi, Team Lead, Division of Viral Hepatitis, Centers
India for Disease Control and Prevention, Atlanta,
Mark A. Gilger, MD Corynebacterium diphtheriae Georgia
Professor of Pediatrics, Baylor College of Hepatitis B and Hepatitis D Viruses
Medicine; Pediatrician-in-Chief, Emeritus, Bruce J. Gutelius, MD, MPH
The Children’s Hospital of San Antonio, Team Lead, Enteric Diseases Epidemiology Christopher J. Harrison, MD
CHRISTUS Health, San Antonio, Texas Branch, Division of Foodborne, Waterborne, Professor of Pediatrics, University of Missouri
Helicobacter pylori; Other Gastric and and Environmental Diseases, National Center at Kansas City School of Medicine; Division of
Enterohepatic Helicobacter Species for Emerging and Zoonotic Infectious Diseases, Infectious Diseases, Children’s Mercy–Kansas
Centers for Disease Control and Prevention, City, Kansas City, Missouri
Carol A. Glaser, MD, DVM, MPVM Atlanta, Georgia Chronic Meningitis; Recurrent Meningitis;
Medical Officer, California Department of Other Vibrio Species Focal Suppurative Infections of the Nervous
Public Health, Richmond, California System
Encephalitis; Parainfectious and Postinfectious Julie R. Gutman, MD, MSc
Neurologic Syndromes Strategic and Applied Science Team Lead, David B. Haslam, MD
Malaria Branch, Center for Global Health, Professor of Pediatrics, University of
Jane M. Gould, MD Centers for Disease Control and Prevention, Cincinnati College of Medicine; Division of
Medical Director, Healthcare-Associated Atlanta, Georgia Infectious Diseases, Cincinnati Children’s
Infections/Antimicrobial Resistance Program, Plasmodium Species (Malaria); Antiparasitic Hospital, Cincinnati, Ohio
Philadelphia Department of Public Health, Agents Classification of Streptococci; Enterococcus
Philadelphia, Pennsylvania Species; Viridans Streptococci, Abiotrophia
Healthcare-Associated Infections Aron J. Hall, DVM, MSPH and Granulicatella Species, and Streptococcus
Norovirus Epidemiology Team Lead, Division bovis Group; Groups C and G Streptococci;
James Graziano, MS, MPH of Viral Diseases, Centers for Disease Control Other Gram-Positive, Catalase-Negative Cocci:
Biologist, Viral Special Pathogens Branch, and Prevention, Atlanta, Georgia Leuconostoc and Pediococcus Species and Other
Centers for Disease Control and Prevention, Enteric Diseases Transmitted Through Food, Genera
Atlanta, Georgia Water, and Zoonotic Exposures; Caliciviruses
Filoviruses and Arenaviruses

xii
 Contributors

Julia C. Haston, MD, MSc Peter J. Hotez, MD, PhD Sophonie Jean, PhD, D(ABMM)
EIS Officer, Division of Foodborne, Dean, National School of Tropical Medicine, Assistant Professor of Pathology and
Waterborne, and Environmental Diseases, Professor of Pediatrics and Molecular Virology Laboratory Medicine, The Ohio State
National Center for Emerging and Zoonotic & Microbiology, Head, Section of Pediatric University College of Medicine; Clinical
Infectious Diseases, Centers for Disease Tropical Medicine, Baylor College of Medicine; Microbiology and Immunoserology
Control and Prevention, Atlanta, Georgia Texas Children’s Hospital Endowed Chair Laboratories, Nationwide Children’s Hospital,
Trypanosoma Species (Trypanosomiasis) of Tropical Pediatrics, Director, Center for Columbus, Ohio
Vaccine Development, Texas Children’s Enterobacter, Cronobacter, and Pantoea
Sarah.J. Hawkes, MBBS, PhD Hospital, Baker Institute Fellow in Disease and Species; Citrobacter Species; Less Commonly
Professor of Global Public Health, Institute Poverty, Rice University, Houston, Texas Encountered Enterobacterales
for Global Health, University College London, Classification of Parasites; Intestinal
London, United Kingdom Nematodes Ravi Jhaveri, MD
Treponema pallidum (Syphilis) Professor of Pediatrics, Northwestern
Katherine K. Hsu, MD, MPH University Feinberg School of Medicine;
Taylor Heald-Sargent, MD, PhD Professor of Pediatrics–Pediatric Infectious Interim Division Head, Division of Pediatric
Assistant Professor of Pediatrics, Northwestern Diseases, Boston University Medical Center, Infectious Diseases, Ann & Robert H. Lurie
University Feinberg School of Medicine; Boston, Massachusetts; Medical Director, Children’s Hospital of Chicago, Chicago,
Attending Physician, Division of Infectious Division of STD Prevention, Bureau of Illinois
Diseases, Ann & Robert H. Lurie Children’s Infectious Diseases Prevention, Response, and Fever Without Localizing Signs
Hospital of Chicago, Chicago, Illinois Services, Massachusetts Department of Public
Streptococcus pyogenes (Group A Streptococcus) Health, Jamaica Plain, Massachusetts Kateřina Jirků-Pomajbíková, DVM, PhD
Neisseria gonorrhoeae; Other Neisseria Species Researcher, Institute of Parasitology, Biology
†J. Owen Hendley, MD Centre of the Czech Academy of Sciences,
Professor of Pediatric Infectious Diseases, Felicia Scaggs Huang, MD, MSc České Budějovice, Czech Republic
University of Virginia, Charlottesville, Virginia Assistant Professor of Pediatrics, University Balantioides coli (Formerly Balantidium coli)
Rhinoviruses of Cincinnati College of Medicine; Attending
Physician, Division of Infectious Diseases, Nadia A. Kadry, PhD
Adam L. Hersh, MD, PhD Cincinnati Children’s Hospital Medical Center, Cell and Molecular Biology, University of
Professor of Pediatrics, University of Utah Cincinnati, Ohio Pennsylvania, Philadelphia, Pennsylvania
School of Medicine; Pediatric Infectious Clinical Syndromes of Device-Associated Haemophilus influenzae
Diseases, Primary Children’s Hospital and the Infections
University of Utah Health, Salt Lake City, Utah Mary L. Kamb, MD, MPH
Principles of Anti-Infective Therapy David A. Hunstad, MD Team Lead, Elimination and Control
Professor of Pediatrics and Molecular Epidemiology, Parasitic Diseases Branch,
Joseph A. Hilinski, MD Microbiology, Washington University School Division of Parasitic Diseases and Malaria,
Clinical Associate Professor of Pediatrics, of Medicine; Service Chief, Pediatric Infectious Centers for Disease Control and Prevention,
University of Washington School of Medicine, Diseases, St. Louis Children’s Hospital, St. Louis, Atlanta, Georgia
Seattle, Washington; Attending Physician, Missouri Blood and Tissue Nematodes: Filarial Worms
Pediatric Infectious Diseases/Children’s Infectious Complications in Special Hosts
Infections and Immune Deficiency Clinic, St. Ronak K. Kapadia, MD, MSc, BSc
Luke’s Children’s Hospital, Boise, Idaho W. Garrett Hunt, MD, MPH, DTM&H Assistant Professor of Clinical Neurosciences,
Myocarditis; Pericarditis Associate Professor of Pediatrics, The Ohio University of Calgary, Calgary, Alberta, Canada
State University College of Medicine; Section Parainfectious and Postinfectious Neurologic
Susan L. Hills, MBBS, MTH of Infectious Diseases, Nationwide Children’s Syndromes
Medical Epidemiologist, Arboviral Diseases Hospital, Columbus, Ohio
Branch, Centers for Disease Control and Enterobacter, Cronobacter, and Pantoea Species Ben Z. Katz, MD
Prevention, Fort Collins, Colorado Professor of Pediatrics, Northwestern
Flaviviruses Loris Y. Hwang, MD University Feinberg School of Medicine;
Associate Professor of Pediatrics, David Attending Physician, Division of Infectious
David K. Hong, MD Geffen School of Medicine at the University of Diseases, Ann & Robert H. Lurie Children’s
Associate Professor (Affiliated) of Pediatrics– California, Los Angeles; Division of Adolescent Hospital of Chicago, Chicago, Illinois
Infectious Diseases, Stanford University School and Young Adult Medicine, University of Epstein-Barr Virus (Mononucleosis and
of Medicine, Stanford, California; Head of California Los Angeles, Mattel Children’s Lymphoproliferative Disorders)
Viral Respiratory Infections R&D, Janssen Hospital UCLA, Los Angeles, California
Pharmaceutical Companies of Johnson & Human Papillomavirus Sophie E. Katz, MD, MPH
Johnson, South San Francisco, California; Staff Assistant Professor of Pediatrics, Division of
Physician, Pediatric Infectious Diseases, Santa Christelle M. Ilboudo, MD Infectious Diseases, Vanderbilt University
Clara Valley Medical Center, San Jose, California Assistant Professor of Child Health, University Medical Center, Nashville, Tennessee
Osteomyelitis; Infectious and Inflammatory of Missouri Health Care, Columbia, Missouri Myositis, Pyomyositis, and Necrotizing
Arthritis; Diskitis Other Gram-Positive Bacilli Fasciitis; Transient Synovitis

Preeti Jaggi, MD Ishminder Kaur, MD

Associate Professor of Pediatrics, Emory Assistant Professor of Pediatrics, David
University School of Medicine; Division of Geffen School of Medicine at the University
Infectious Diseases, Children’s Healthcare of of California, Los Angeles; Attending
Atlanta, Atlanta, Georgia Physician, Division of Infectious Diseases,
Kawasaki Disease UCLA Mattel Children’s Hospital, Los
Angeles, California
Mucocutaneous Symptom Complexes;
Infections Related to Burns; Topical
Antimicrobial Agents
†Deceased.

xiii
 Contributors

Gilbert J. Kersh, PhD Andrew T. Kroger, MD, MPH Eloisa Llata, MD, MPH
Branch Chief, Rickettsial Zoonoses Branch, Medical Officer, National Center for Medical Epidemiologist, Division of STD
Centers for Disease Control and Prevention, Immunization and Respiratory Diseases, Prevention, Centers for Disease Control and
Atlanta, Georgia Centers for Disease Control and Prevention, Prevention, Atlanta, Georgia
Coxiella burnetii (Q fever) Atlanta, Georgia Pelvic Inflammatory Disease
Active Immunization
Muhammad Ali Khan, MD, MPH Kevin Lloyd, MD
Assistant Professor of Pediatrics, George Matthew P. Kronman, MD, MSCE Research Instructor, Department of
Washington University School of Associate Professor of Pediatrics, University of Pediatrics, George Washington University
Medicine and Health Sciences; Division of Washington School of Medicine; Division of School of Medicine and Health Sciences;
Gastroenterology, Hepatology, and Nutrition, Infectious Diseases, Seattle Children’s Hospital, Fellow, Division of Infectious Diseases,
Children’s National Hospital, Washington, Seattle, Washington Children’s National Hospital, Washington,
District of Columbia Endocarditis and Other Intravascular District of Columbia
Chronic Hepatitis Infections Appendicitis

Ananta Khurana, MD, DNB, MNAMS Leah Lalor, MD Katrina Loh, MD

Professor of Dermatology, Dr RML Hospital, Assistant Professor of Dermatology/Pediatrics, Pediatric Gastroenterology Fellow, Department
ABVIMS, Delhi, India Medical College of Wisconsin; Children’s of Gastroenterology, Hepatology, and
Superficial Fungal Infections Wisconsin Clinics–Milwaukee, Milwaukee, Nutrition, Children’s National Hospital,
Wisconsin Washington, District of Columbia
David W. Kimberlin, MD Urticaria and Erythema Multiforme Acute Hepatitis; Chronic Hepatitis
Professor and Vice Chair for Clinical and
Translational Research, Co-Director, Division Christine T. Lauren, MD, MHA Sarah S. Long, MD
of Pediatric Infectious Diseases, Department Associate Professor of Dermatology, Columbia Professor of Pediatrics, Drexel University
of Pediatrics, University of Alabama at University College of Physicians and Surgeons; College of Medicine; Emeritus Chief, Section of
Birmingham Heersink School of Medicine Columbia University Irving Medical Center, Infectious Diseases, St. Christopher’s Hospital
and the Children’s Hospital of Alabama, New York, New York for Children, Philadelphia, Pennsylvania
Birmingham, Alabama Papules, Nodules, and Ulcers Mucocutaneous Symptom Complexes;
Introduction to Herpesviridae; Herpes Simplex Prolonged, Recurrent, and Periodic Fever
Virus; Antiviral Agents Amy Leber, PhD Syndromes; Respiratory Tract Symptom
Professor of Pediatrics and Pathology, The Complexes; Bordetella pertussis (Pertussis) and
Bruce Klein, MD Ohio State University College of Medicine; Other Bordetella Species; Anaerobic Bacteria:
Professor of Pediatrics, Medicine, and Medical Director, Clinical Microbiology and Clinical Concepts and the Microbiome in
Microbiology, University of Wisconsin– Immunoserology, Department of Pathology Health and Disease; Clostridium botuli-
Madison, Madison, Wisconsin and Laboratory Medicine, Nationwide num (Botulism); Use of Common Clinical
Blastomyces Species (Blastomycosis) Children’s Hospital, Columbus, Ohio Laboratory Tests to Assess Infectious and
Klebsiella and Raoultella Species; Less Inflammatory Diseases; Principles of Anti-
Miwako Kobayashi, MD, MPH Commonly Encountered Nonenteric Gram- Infective Therapy
Medical Epidemiologist, Respiratory Diseases Negative Bacilli; Eikenella, Pasteurella, and
Branch, Centers for Disease Control and Chromobacterium Species Benjamin A. Lopman, PhD, MSc
Prevention, Atlanta, Georgia Professor of Epidemiology and Environmental
Chlamydophila (Chlamydia) psittaci Eyal Leshem, MD, DTMH Health, Rollins School of Public Health, Emory
(Psittacosis) Clinical Associate Professor of Medicine, Tel University, Atlanta, Georgia
Aviv University, Tel Aviv, Israel; Consultant, Viral Gastroenteritis
Larry K. Kociolek, MD, MSCI Division of Infectious Diseases, Sheba Medical
Assistant Professor of Pediatrics, Northwestern Center, Tel Hashomer, Israel Yalda C. Lucero, MD, PhD
University Feinberg School of Medicine; Medical Viral Gastroenteritis Associate Professor of Pediatric
Director of Infection Prevention and Control, Gastroenterology, Microbiology and Micology
Pediatric Infectious Diseases, Ann & Robert H. David B. Lewis, MD Program, Institute of Biomedical Science and
Lurie Children’s Hospital of Chicago, Chicago, Professor of Pediatrics, Stanford University Department of Pediatrics, Hospital Roberto
Illinois School of Medicine, Stanford, California; del Río; Faculty of Medicine, University of
Clostridioides difficile Chief, Division of Allergy, Immunology, and Chile, Hospital Roberto del Río; Pediatric
Rheumatology, Attending Physician, Lucile Salter Gastroenterology, Clínica Alemana de
Andrew Y. Koh, MD Packard Children’s Hospital, Palo Alto, California Santiago, Facultad de Medicina, Clínica
Associate Professor of Pediatrics, University Hemophagocytic Lymphohistiocytosis and Alemana-Universidad del Desarrollo, Santiago,
of Texas Southwestern Medical Center; Macrophage Activation Syndrome; Infectious Chile
Director, Pediatric Hematopoietic Stem Cell Complications of Deficiencies of Cell-Mediated Aeromonas Species
Transplantation, Children’s Health, Dallas, Texas Immunity Other Than AIDs: Primary
Risk Factors and Infectious Agents in Children Immunodeficiencies Debra J. Lugo, MD
With Cancer: Fever and Granulocytopenia; Assistant Professor of Pediatrics, Duke
Clinical Syndromes of Infection in Children Robyn A. Livingston, MD, MPH University School of Medicine; Division of
With Cancer Associate Professor of Pediatrics, University of Infectious Diseases, Duke Children’s Hospital
Missouri at Kansas City School of Medicine; and Health Center, Durham, North Carolina
Karen L. Kotloff, MD Associate Professor of Pediatric Infectious Antifungal Agents
Professor of Pediatrics–Infectious Diseases and Diseases, Children’s Mercy–Kansas City,
Tropical Pediatrics, Department of Medicine, Kansas City, Missouri Jorge Luján-Zilbermann, MD
University of Maryland School of Medicine; Recurrent Meningitis Attending Physician, Division of Infectious
Principal Investigator, Center for Vaccine Diseases, Johns Hopkins All Children’s
Development and Global Health, Baltimore, Hospital, Saint Petersburg, Florida
Maryland Infections in Hematopoietic Cell Transplant
Abdominal Symptom Complexes; Recipients
Inflammatory Enterocolitis

xiv
 Contributors

Yvonne A. Maldonado, MD Kathleen A. McGann, MD Melissa B. Miller, PhD, D(ABMM), F(AAM)

Senior Associate Dean for Faculty Development Professor of Pediatrics, Duke University Professor of Pathology and Laboratory
and Diversity, Taube Professor of Global Medical Center; Attending Physician, Section Medicine, University of North Carolina School
Health and Infectious Diseases, Professor of of Infectious Diseases, Duke Children’s of Medicine; Director, Clinical Microbiology
Pediatrics and Health Research and Policy, Hospital, Durham, North Carolina and Molecular Microbiology Laboratories,
Stanford University School of Medicine; Chief, Respiratory Tract Symptom Complexes UNC Medical Center, Chapel Hill, North
Division of Pediatric Infectious Diseases, Carolina
Medical Director, Infection Prevention and Lucy A. McNamara, PhD Mechanisms and Detection of Antimicrobial
Control and Attending Physician, Lucile Epidemiologist, Division of Bacterial Diseases, Resistance
Packard Children’s Hospital at Stanford, National Center for Immunization and
Stanford, California Respiratory Diseases, Centers for Disease Hilary Miller-Handley, MD
Rubella Virus; Mumps Virus; Rubeola Control and Prevention, Atlanta, Georgia Clinical Instructor, Department of Pediatrics,
Virus: Measles and Subacute Sclerosing Principles of Epidemiology and Public Health University of Cincinnati College of Medicine;
Panencephalitis; Polioviruses Division of Infectious Diseases, Cincinnati
Debrah Meislich, MD Children’s Hospital Medical Center,
John J. Manaloor, MD Assistant Professor of Pediatrics, Pediatric Cincinnati, Ohio
Associate Professor of Pediatrics, Baylor Clerkship Director, Cooper Medical School Infectious Complications in Special Hosts
College of Medicine, Division of Pediatric of Rowan University; Attending Physician,
Infectious Diseases, Director of Antimicrobial Pediatric Infectious Diseases, Cooper Eric Mintz, MD, MPH
Stewardship, Children’s Hospital of San University Hospital, Camden, New Jersey Medical Epidemiologist, Waterborne Diseases
Antonio, San Antonio, Texas Anaerobic Cocci; Anaerobic Gram- Prevention Branch, Centers for Disease Control
Agents of Eumycotic Mycetoma: Positive Nonsporulating Bacilli (Including and Prevention, Atlanta, Georgia
Pseudallescheria boydii and Scedosporium Actinomycosis) Vibrio cholerae (Cholera)
apiospermum; Laboratory Diagnosis of
Infection Due to Bacteria, Fungi, Parasites, and H. Cody Meissner, MD Parvathi Mohan, MD, MBBS
Rickettsiae Professor of Pediatrics, Tufts University Professor of Pediatrics, George Washington
School of Medicine; Chief, Pediatric Infectious University School of Medicine and Health
Kalpana Manthiram, MD, MSCI Diseases, Department of Pediatrics, Tufts Sciences; Director of Hepatology, Department
Assistant Clinical Investigator, National Institute Medical Center, Boston, Massachusetts of Gastroenterology, Hepatology, and
of Allergy and Infectious Diseases, National Passive Immunization; Bronchiolitis; Nutrition, Children’s National Hospital,
Institutes of Health, Bethesda, Maryland Respiratory Syncytial Virus Washington, District of Columbia
Prolonged, Recurrent, and Periodic Fever Chronic Hepatitis
Syndromes Asuncion Mejias, MD, PhD, MsCS
Associate Professor of Pediatrics, The Ohio Susan P. Montgomery, DVM, MPH
Stacey W. Martin, MSc State University College of Medicine; Division Parasitic Diseases Branch, Centers for Disease
Health Scientist, Division of Vector-Borne of Infectious Diseases, Nationwide Children’s Control and Prevention, Atlanta, Georgia
Diseases, Centers for Disease Control and Hospital and Principal Investigator, Department Diphyllobothriidae, Dipylidium and
Prevention, Fort Collins, Colorado of Pediatrics, Abigail Wexner Research Institute at Hymenolepis Species; Blood Trematodes:
Principles of Epidemiology and Public Health Nationwide Children’s Hospital, Columbus, Ohio Schistosomiasis
Fever and the Inflammatory Response;
Roshni Mathew, MD Parainfluenza Viruses Jose G. Montoya, MD
Clinical Associate Professor of Pediatrics, Director of Laboratory Medicine, Dr. Jack
Stanford University School of Medicine, Jussi Mertsola, MD S. Remington Laboratory for Specialty
Stanford, California; Co-Medical Director, Professor of Pediatrics and Adolescent Medicine, Diagnostics, Palo Alto, California
Infection Prevention and Control, Lucile Turku University Hospital, Turku, Finland Toxoplasma gondii (Toxoplasmosis)
Packard Children’s Hospital, Palo Alto, Bordetella pertussis (Pertussis) and Other
California Bordetella Species Anne C. Moorman, MPH
Osteomyelitis; Infectious and Inflammatory Epidemiologist, Division of Viral Hepatitis,
Arthritis; Diskitis Kevin Messacar, MD Centers for Disease Control and Prevention,
Associate Professor of Pediatrics, University Atlanta, Georgia
Tony Mazzulli, MD of Colorado School of Medicine; Division Hepatitis C Virus
Professor of Laboratory Medicine and of Infectious Diseases, Children’s Hospital
Pathobiology, University of Toronto Faculty of Colorado, Aurora, Colorado Pedro L. Moro, MD, MPH
Medicine; Microbiologist-in-Chief, Department Introduction to Picornaviridae; Enteroviruses Medical Epidemiologist, Immunization
of Microbiology, Mount Sinai Hospital/ and Parechoviruses Safety Office, Division of Healthcare Quality
University Health Network, Toronto, Ontario, Promotion, National Center for Emerging
Canada Mohammad Nael Mhaissen, MD and Zoonotic Infectious Diseases, Centers
Laboratory Diagnosis of Infection Due to Medical Director, Pediatric Infectious Diseases, for Disease Control and Prevention, Atlanta,
Viruses, Chlamydia, and Mycoplasma Valley Children’s Healthcare, Madera, Georgia
California Echinococcus Species: Agents of Echinococcosis
Elizabeth J. McFarland, MD Cryptosporidium Species; Cystoisospora
Professor of Pediatrics, University of Colorado (Isospora) and Cyclospora Species Anna-Barbara Moscicki, MD
School of Medicine; Chief, Section of Infectious Professor of Pediatrics, David Geffen School
Diseases, Children’s Hospital Colorado, Marian G. Michaels, MD, MPH of Medicine at the University of California Los
Aurora, Colorado Professor of Pediatrics, University of Pittsburgh Angeles; Division of Adolescent and Young
Diagnosis and Clinical Manifestations of HIV School of Medicine; Division of Pediatric Adult Medicine, Mattel Children’s Hospital
Infection Infectious Diseases, UPMC Children’s Hospital UCLA, Los Angeles, California
of Pittsburgh, Pittsburgh, Pennsylvania Human Papillomavirus
Eosinophilic Meningitis; Infections in Solid
Organ Transplant Recipients

xv
 Contributors

William J. Muller, MD, PhD William Nicholson, PhD Christopher P. Ouellette, MD

Associate Professor of Pediatrics, Northwestern Activity Chief, Rickettsial Zoonoses Branch, Assistant Professor of Pediatrics, The Ohio
University Feinberg School of Medicine; Centers for Disease Control and Prevention, State University College of Medicine; Division
Attending Physician, Division of Infectious Atlanta, Georgia of Infectious Diseases and Host Defense
Diseases, Ann & Robert H. Lurie Children’s Family Anaplasmataceae (Anaplasmosis, Program, Nationwide Children’s Hospital,
Hospital of Chicago, Chicago, Illinois Ehrlichiosis, Neorickettsiosis, and Columbus, Ohio
Epstein-Barr Virus (Mononucleosis and Neoehrlichiosis) Proteus, Providencia, and Morganella Species
Lymphoproliferative Disorders)
Amy Jo Nopper, MD Christopher D. Paddock, MD, MS, MPHTM
Angela L. Myers, MD, MPH Professor of Pediatrics, University of Missouri Research Medical Officer, Rickettsial Zoonoses
Professor of Pediatrics, University of Missouri- at Kansas City School of Medicine; Division Branch, Centers for Disease Control and
Kansas City; Director, Division of Infectious Director, Dermatology, Children’s Mercy– Prevention, Atlanta, Georgia
Diseases, Children’s Mercy–Kansas City, Kansas City, Kansas City, Missouri Rickettsia rickettsii (Rocky Mountain Spotted
Kansas City, Missouri Superficial Bacterial Skin Infections and Fever)
Abdominal and Retroperitoneal Cellulitis
Lymphadenopathy; Localized Lymphadenitis, Debra L. Palazzi, MD, MEd
Lymphadenopathy, and Lymphangitis Laura E. Norton, MD Professor of Pediatrics, Baylor College of
Assistant Professor of Pediatrics, University Medicine; Chief, Pediatric Infectious Diseases
Simon Nadel, MBBS, MRCP of Minnesota Medical School, Minneapolis, Clinic, Texas Children’s Hospital, Houston,
Consultant Paediatric Intensivist, St Mary’s Minnesota Texas
Hospital and Imperial College, London, United Arcanobacterium haemolyticum; Other Eosinophilic Meningitis
Kingdom Corynebacteria
Acute Bacterial Meningitis Beyond the Suresh Kumar Panuganti, MBBS, DCH,
Neonatal Period Theresa J. Ochoa, MD DNB (Paediatrics)
Associate Professor, Instituto de Medicina Fellow in Pediatric Critical Care Medicine,
Jennifer Lynn Nayak, MD Tropical Alexander von Humboldt, Consultant Pediatric Intensivist, Department
Associate Professor of Pediatrics, University of Universidad Peruana Cayetano Heredia, Lima, of Pediatrics, Yashoda Hospital, Somajiguda,
Rochester School of Medicine and Dentistry; Peru; Associate Professor of Epidemiology, Hyderabad, India
Division of Infectious Diseases, Golisano Center for Infectious Diseases, University Acute Bacterial Meningitis Beyond the
Children’s Hospital, University of Rochester of Texas Health Science Center at Houston, Neonatal Period
Medical Center, Rochester, New York Houston, Texas
Human Herpesvirus 6 and 7 (Roseola, Yersinia Species Diane E. Pappas, MD, JD
Exanthem Subitum); Human Herpesvirus 8 Professor of Pediatrics, University of Virginia
(Kaposi Sarcoma-Associated Herpesvirus) Liset Olarte, MD, MSc School of Medicine; Division of General
Assistant Professor of Pediatrics, University of Pediatrics, University of Virginia Health
Michael Noel Neely, MSc, MD Missouri at Kansas City School of Medicine; System, Charlottesville, Virginia
Professor of Pediatrics, Keck School of Division of Infectious Diseases, Children’s The Common Cold; Rhinoviruses
Medicine, University of Southern California; Mercy–Kansas City, Kansas City, Missouri
Chief, Pediatric Infectious Diseases, Children’s Streptococcus pneumoniae; Bacillus Species Michal Paret, MD
Hospital Los Angeles, Los Angeles, California (Including Anthrax) Division of Pediatric Infectious Diseases,
Pharmacokinetic and Pharmacodynamic Department of Pediatrics, NYU Langone
Basis of Optimal Antimicrobial Therapy; Timothy R. Onarecker, MD Health/Hassenfeld Children’s Hospital, New
Antibacterial Agents Assistant Professor of Pediatrics, University York, New York
of Arkansas for Medical Sciences; Division Epididymitis, Orchitis, and Prostatitis
Karen P. Neil, MD, MSPH of Infectious Diseases, Arkansas Children’s
Epidemiologist, Division of Foodborne, Hospital, Little Rock, Arkansas Daniel M. Pastula, MD, MHS
Waterborne, and Environmental Diseases, Aseptic and Viral Meningitis Associate Professor of Neurology, Medicine
Centers for Disease Control and Prevention, (Infectious Diseases and Epidemiology),
Atlanta, Georgia Walter A. Orenstein, MD, DSc (Hon) University of Colorado School of Medicine,
Enteric Diseases Transmitted Through Food, Professor of Medicine, Pediatrics, Aurora, Colorado
Water, and Zoonotic Exposures Epidemiology, and Global Health, Emory Parainfectious and Postinfectious Neurologic
University School of Medicine; Associate Syndromes
Christina A. Nelson, MD, MPH Director, Emory Vaccine Center, Atlanta,
Medical Officer, Division of Vector-Borne Georgia Thomas F. Patterson, MD
Diseases, Centers for Disease Control and Active Immunization Professor of Medicine, University of Texas
Prevention, Fort Collins, Colorado Health Sciences Center at San Antonio; Chief,
Francisella tularensis (Tularemia) Miguel O’Ryan, MD Division of Infectious Diseases, Director, San
Professor, Microbiology and Mycology Antonio Center for Medical Mycology, UT
Noele P. Nelson, MD, PhD, MPH Program, Institute of Biomedical Sciences, Health San Antonio, San Antonio, Texas
Medical Epidemiologist, Division of Viral Faculty of Medicine, University of Chile, Classification of Fungi; Agents of
Hepatitis, Centers for Disease Control and Santiago, Chile Hyalohyphomycosis and Phaeohyphomycosis;
Prevention, Atlanta, Georgia Yersinia Species; Aeromonas Species Agents of Mucormycosis; Malassezia Species;
Hepatitis A Virus Sporothrix schenckii Complex (Sporotrichosis);
William R. Otto, MD Cryptococcus Species
Megin Nichols, DVM, MPH, DACVPM Attending Physician, Pediatrics, Division of
Epidemiologist, Division of Foodborne, Infectious Diseases, The Children’s Hospital of Brett W. Petersen, MD, MPH
Waterborne, and Environmental Diseases, Philadelphia, Philadelphia, Pennsylvania Captain, US Public Health Service, Poxvirus
Centers for Disease Control and Prevention, Candida Species and Rabies Branch, Division of High
Atlanta, Georgia Consequence Pathogens and Pathology,
Enteric Diseases Transmitted Through Food, National Center for Emerging and Zoonotic
Water, and Zoonotic Exposures Infectious Diseases, Centers for Disease
Control and Prevention, Atlanta, Georgia
Poxviridae

xvi
 Contributors

Mikael Petrosyan, MD, MBA Susan M. Poutanen, MD, MPH Adam J. Ratner, MD, MPH
Associate Professor of General and Thoracic Associate Professor of Laboratory Medicine Associate Professor of Pediatrics and
Surgery, George Washington University School and Pathobiology & Medicine, University Microbiology, NYU Grossman School
of Medicine; Associate Chief, Department of Toronto Faculty of Medicine; Medical of Medicine; Chief, Division of Pediatric
of General and Thoracic Surgery, Children’s Microbiologist & Infectious Diseases Physician, Infectious Diseases, NYU Langone Health, New
National Medical Center, Washington, District Mount Sinai Hospital & University Health York, New York
of Columbia Network, Toronto, Ontario, Canada Sexually Transmitted Infection Syndromes;
Appendicitis Human Coronaviruses Epididymitis, Orchitis, and Prostatitis

Larry K. Pickering, MD Ann M. Powers, PhD Sarah A. Rawstron, MD

Adjunct Professor of Pediatrics, Emory Lead, Virology Team, Arboviral Diseases Associate Professor of Pediatrics, Hackensack
University School of Medicine, Atlanta, Branch, Centers for Disease Control and Meridian School of Medicine; Attending
Georgia Prevention, Fort Collins, Colorado Physician, Infectious Diseases, K. Hovnanian
Active Immunization Togaviridae: Alphaviruses Children’s Hospital at Jersey Shore University
Medical Center, Neptune, New Jersey
Talia Pindyck, MD, MPH Nina Salinger Prasanphanich, MD, PhD Treponema pallidum (Syphilis); Other
Medical Epidemiologist, Waterborne Disease Pediatric Infectious Diseases Fellow, Treponema Species
Prevention Branch, Centers for Disease Control Cincinnati Children’s Hospital Medical Center,
and Prevention, Atlanta, Georgia Cincinnati, Ohio Jennifer S. Read, MD, MPH, DTM&H
Vibrio cholerae (Cholera) Giardia intestinalis (Giardiasis) Clinical Professor of Pediatrics, University of
Vermont Medical Center, Burlington, Vermont
Swetha Pinninti, MD Bobbi S. Pritt, MD, MSc, (D)TMH Epidemiology and Prevention of HIV Infection
Assistant Professor, University of Alabama at Professor of Laboratory Medicine and in Infants, Children, and Adolescents
Birmingham Heersink School of Medicine; Pathology, Director, Clinical Parasitology,
Division of Infectious Diseases, Children’s Mayo Clinic, Minneapolis, Minnesota Ryan F. Relich, PhD, D(ABMM),
Hospital of Alabama at the University of Family Anaplasmataceae (Anaplasmosis, MLS(ASCP)CMSMCM
Alabama, Birmingham, Alabama Ehrlichiosis, Neorickettsiosis, and Associate Professor of Clinical Pathology and
Viral Infections in the Fetus and Neonate Neoehrlichiosis) Laboratory Medicine, Indiana University
School of Medicine; Medical Director,
Laure F. Pittet, MD, PhD Charles G. Prober, MD Division of Clinical Microbiology, Indiana
Clinical Research Fellow, Infectious Diseases Professor of Pediatrics, Microbiology, and University Health; Medical Director, Clinical
Unit, Department of General Paediatrics, Immunology, Founding Executive Director, Microbiology and Serology Laboratories,
University Hospitals of Geneva, Faculty of Stanford Center for Health Education, Senior Eskenazi Health, Indianapolis, Indiana
Medicine of the University of Geneva, Geneva, Associate Vice Provost for Health Education, Laboratory Diagnosis of Infection Due to
Switzerland; Honorary Fellow, Department Stanford University School of Medicine, Bacteria, Fungi, Parasites, and Rickettsiae
of Paediatrics, The University of Melbourne; Stanford, California
Clinical Research Fellow, Infectious Diseases Introduction to Herpesviridae; Herpes Simplex Megan E. Reller, MD, PhD, MPH, DTM&H
Group, Murdoch Children’s Research Institute, Virus Associate Professor of Medicine, Duke
Parkville, Victoria, Australia University School of Medicine; Division of
Mycobacterium Nontuberculosis Species Neha Puar, MD Infectious Diseases and International Health,
Clinical Assistant Professor of Pediatrics, Duke Hubert-Yeargan Center for Global
Paul J. Planet, MD, PhD University of Missouri at Kansas City School Health and Duke Global Health Institute,
Assistant Professor of Pediatrics, Perelman of Medicine; Children’s Mercy–Kansas City, Durham, North Carolina
School of Medicine at the University of Kansas City, Missouri Salmonella Species
Pennsylvania; Attending Physician, Division Superficial Bacterial Skin Infections and
of Infectious Diseases, Children’s Hospital of Cellulitis Candice L. Robinson, MD, MPH
Philadelphia, Philadelphia, Pennsylvania Medical Officer, National Center for
Pseudomonas aeruginosa Laura A.S. Quilter, MD, MPH Immunization and Respiratory Diseases,
Medical Officer, Division of STD Prevention, Centers for Disease Control and Prevention,
Andrew J. Pollard, MBBS, BSC, Centers for Disease Control and Prevention, Atlanta, Georgia
MRCP(UK), DIC, PhD Atlanta, Georgia Active Immunization
Professor of Paediatric Infection and Genitourinary Skin and Mucous Membrane
Immunity, Oxford Vaccine Group, Infections and Inguinal Lymphadenopathy; José R. Romero, MD
Department of Paediatrics, University of Trichomonas vaginalis Professor of Pediatrics, Division of Pediatric
Oxford, Oxford, United Kingdom Infectious Diseases, University of Arkansas for
Neisseria meningitidis Octavio Ramilo, MD Medical Sciences; Arkansas Secretary of Health,
Henry G. Cramblett Chair in Pediatric Director, Arkansas Department of Health,
Klara M. Posfay-Barbe, MD Infectious Diseases and Professor, Department Little Rock, Arkansas
Professor, Department of Pediatrics, of Pediatrics, The Ohio State University College Aseptic and Viral Meningitis
Gynecology, and Obstetrics, University of of Medicine; Chief, Division of Infectious
Geneva School of Medicine; Head, Infectious Diseases, Nationwide Children’s Hospital, David A. Rosen, MD, PhD
Diseases Unit, Children’s Hospital of Geneva, Columbus, Ohio Assistant Professor of Pediatrics and Molecular
University Hospitals of Geneva, Geneva, Fever and the Inflammatory Response; Microbiology, Washington University School
Switzerland Parainfluenza Viruses of Medicine; Division of Infectious Diseases, St.
Eosinophilic Meningitis Louis Children’s Hospital, St. Louis, Missouri
Suchitra Rao, MBBS, MSCS Infectious Complications in Special Hosts
Casper S. Poulsen, PhD Associate Professor of Pediatrics, University
Faculty of Health and Medical Sciences, of Colorado School of Medicine; Divisions of
University of Copenhagen; Novo Nordisk Infectious Diseases and Hospital Medicine,
Foundation Center for Basic Metabolic Children’s Hospital Colorado, Aurora,
Research, Copenhagen, Denmark Colorado
Endolimax nana BK, JC, and Other Human Polyomaviruses;
Influenza Viruses

xvii
 Contributors

Shannon A. Ross, MD, MSPH Kabir Sardana, MD, DNB, MNAMS Samir S. Shah, MD, MSCE
Associate Professor of Pediatrics, University Professor and Director of Dermatology, Dr Professor of Pediatrics, University of
of Alabama at Birmingham Heersink School RML Hospital, ABVIMS, Delhi, India Cincinnati College of Medicine; Director,
of Medicine; Division of Infectious Diseases, Superficial Fungal Infections Division of Hospital Medicine, Attending
Children’s Hospital of Alabama at the Physician in Infectious Diseases and Hospital
University of Alabama, Birmingham, Alabama Jason B. Sauberan, PharmD Medicine, James M. Ewell Endowed Chair,
Cytomegalovirus Clinical Research Pharmacist, Neonatal Cincinnati Children’s Hospital Medical Center,
Research Institute, Sharp Mary Birch Hospital Cincinnati, Ohio
G. Ingrid J.G. Rours, MD, PhD, MSc for Women and Newborns; Consultant Acute Pneumonia and Its Complications;
Pediatrics, Kinderplein, Medical Center Pharmacist, Helen Bernardy Center for Chlamydophila (Chlamydia) pneumoniae;
for Quality of Life; Physician, Medical Medically Fragile Children, Rady Children’s Mycoplasma pneumoniae; Other Mycoplasma
Microbiology and Infectious Diseases, Erasmus Hospital, San Diego, California Species; Ureaplasma urealyticum
Medical Center, Rotterdam, Zuid Holland, the Pharmacokinetic and Pharmacodynamic
Netherlands Basis of Optimal Antimicrobial Therapy; Nader Shaikh, MD, MPH
Chlamydia trachomatis Antibacterial Agents Professor of Pediatrics, University of Pittsburgh
School of Medicine; Attending Physician,
Peter C. Rowe, MD Joshua K. Schaffzin, MD, PhD UMPC Children’s Hospital of Pittsburgh,
Professor of Pediatrics, Johns Hopkins Associate Professor of Pediatrics, University Pittsburgh, Pennsylvania
University School of Medicine; Division of Cincinnati College of Medicine; Division Otitis Media
of Adolescent and Young Adult Medicine, of Infectious Diseases, Director, Infection
Department of Pediatrics, Johns Hopkins Prevention & Control Program, Cincinnati Andi L. Shane, MD, MPH, MSc
Children’s Center, Baltimore, Maryland Children’s Hospital Medical Center, Marcus Professor of Hospital Epidemiology
Myalgic Encephalomyelitis/Chronic Fatigue Cincinnati, Ohio and Infection Prevention, Emory University
Syndrome (ME/CFS) Granulomatous Hepatitis; Acute Pancreatitis; School of Medicine and Children’s Healthcare
Cholecystitis and Cholangitis; Clinical of Atlanta, Atlanta, Georgia
Anne H. Rowley, MD Syndromes of Device-Associated Infections Infections Associated With Group Childcare;
Professor of Pediatrics and Microbiology/ Approach to the Diagnosis and Management of
Immunology, Northwestern University Sarah Schillie, MD, MPH, MBA Gastrointestinal Tract Infections
Feinberg School of Medicine; Attending Medical Epidemiologist, Division of Viral
Physician, Infectious Diseases, The Ann Hepatitis, Centers for Disease Control and Eugene D. Shapiro, MD
& Robert H. Lurie Children’s Hospital of Prevention, Atlanta, Georgia Professor of Pediatrics and Epidemiology
Chicago, Chicago, Illinois Hepatitis B and Hepatitis D Viruses (Microbial Diseases and Investigative
Kawasaki Disease Medicine), Yale University School of Medicine;
Jennifer E. Schuster, MD, MSCI Attending Physician, The Children’s Hospital
Lorry G. Rubin, MD Associate Professor of Pediatrics, University at Yale–New Haven, New Haven, Connecticut
Professor of Pediatrics, Zucker School of of Missouri-Kansas City School of Medicine; Fever Without Localizing Signs; Borrelia burg-
Medicine at Hofstra/Northwell, Hempstead, Division of Infectious Diseases, Children’s dorferi (Lyme Disease)
New York; Director, Infectious Diseases, Cohen Mercy–Kansas City, Kansas City, Missouri
Children’s Medical Center of New York, New Human Metapneumovirus Jana Shaw, MD, MPH
Hyde Park, New York Professor of Pediatrics, SUNY Upstate Medical
Capnocytophaga Species; Francisella tularensis Kevin L. Schwartz, MD, MSc, DTM&H University, Syracuse, New York
(Tularemia); Legionella Species; Streptobacillus Assistant Professor, Dalla Lana School of Infections of the Oral Cavity
moniliformis (Rat-Bite Fever); Other Gram- Public Health, University of Toronto Faculty of
Negative Coccobacilli Medicine; Physician, Infectious Diseases, Unity Avinash K. Shetty, MD
Health Toronto; Infectious Diseases Physician, Associate Dean for Global Health, Professor of
Edward T. Ryan, MD Infection Prevention and Control, Public Pediatrics, Director, Global Health Education,
Professor of Medicine, Harvard Medical Health Ontario, Toronto, Ontario, Canada Wake Forest School of Medicine; Chief, Section
School; Professor of Immunology, Harvard Protection of Travelers of Pediatric Infectious Diseases, Director,
T.H. Chan School of Public Health; Director, Pediatric HIV Program, Atrium Health-Wake
Global Infectious Diseases, Massachusetts Bethany K. Sederdahl, MD, MPH Forest Baptist, Brenner Children’s Hospital,
General Hospital, Boston, Massachusetts Attending Physician, Department of Obstetrics Winston-Salem, North Carolina
Antiparasitic Agents & Gynecology, Christiana Care Healthcare Rubella Virus; Mumps Virus; Rubeola
System, Newark, Delaware Virus: Measles and Subacute Sclerosing
Alexandra Sacharok, BS Other Campylobacter Species Panencephalitis
Graduate Student Researcher, Department
of Pediatrics, The Children’s Hospital of Jose Serpa-Alvarez, MD Timothy R. Shope, MD, MPH
Philadelphia, Philadelphia, Pennsylvania Associate Professor of Medicine–Infectious Professor of Pediatrics, University of Pittsburgh
Classification of Bacteria Diseases, Baylor College of Medicine, Houston, School of Medicine; Attending Physician,
Texas Children’s Hospital of Pittsburgh of UPMC,
Thomas J. Sandora, MD, MPH Taenia solium, Taenia asiatica, and Taenia Pittsburgh, Pennsylvania
Associate Professor of Pediatrics, Harvard saginata: Taeniasis and Cysticercosis; Taenia Infections Associated With Group Childcare
Medical School; Hospital Epidemiologist, (Multiceps) multiceps and Taenia serialis:
Department of Pediatrics, Division of Coenurosis Linda M. Dairiki Shortliffe, MD
Infectious Diseases, Boston Children’s Stanley McCormick Memorial Professor
Hospital, Boston, Massachusetts Kara N. Shah, MD, PhD Emerita, Department of Urology, Stanford
Clostridioides difficile Optima Dermatology, Liberty Township, Ohio University School of Medicine, Stanford,
Urticaria and Erythema Multiforme California
Sarah G.H. Sapp, PhD Urinary Tract Infections, Renal Abscess, and
Biologist, Division of Parasitic Diseases and Other Complex Renal Infections
Malaria, Centers for Disease Control and
Prevention, Atlanta, Georgia
Diphyllobothriidae, Dipylidium and
Hymenolepis Species

xviii
 Contributors

Stanford T. Shulman, MD Lauren L. Smith, MD Jeffrey R. Starke, MD

Virginia H. Rogers Emeritus Professor of Assistant Professor of Pediatrics, Eastern Professor of Pediatrics, Baylor College of
Pediatrics, Division of Infectious Diseases, Virginia Medical School; Medical Director, Medicine; Section of Infectious Diseases, Texas
Northwestern University Feinberg School of Division of Allergy and Immunology, Children’s Hospital, Houston, Texas
Medicine, Ann & Robert H. Lurie Children’s Children’s Hospital of the King’s Daughters, Mycobacterium tuberculosis
Hospital of Chicago, Chicago, Illinois Norfolk, Virginia
Pharyngitis; Streptococcus pyogenes (Group A Evaluation of the Child With Suspected Victoria A. Statler, MD, MSc
Streptococcus) Immunodeficiency; Infectious Complications Associate Professor of Pediatrics, University
of Dysfunction or Deficiency of of Louisville School of Medicine; Physician,
Gail F. Shust, MD Polymorphonuclear and Mononuclear Division of Infectious Diseases, Norton
Clinical Associate Professor of Pediatrics, NYU Phagocytes Children’s Hospital, Louisville, Kentucky
Grossman School of Medicine; Division of Tickborne Infections
Pediatric Infectious Diseases, NYU Langone Eunkyung Song, MD
Health, New York, New York Assistant Professor of Pediatrics, The Ohio William J. Steinbach, MD
Sexually Transmitted Infection Syndromes; State University College of Medicine; Division Robert H. Fiser, Jr., MD Endowed Chair in
Management of HIV Infection of Infectious Diseases, Nationwide Children’s Pediatrics, Chair, Department of Pediatrics,
Hospital, Columbus, Ohio Associate Dean for Child Health, College of
George Kelly Siberry, MD, MPH Serratia Species Medicine, University of Arkansas for Medical
Medical Officer, Office of HIV/AIDS, US Sciences; Pediatrician-in-Chief, Arkansas
Agency for International Development Emily Souder, MD Children’s Hospital, Little Rock, Arkansas
(USAID), Washington, District of Columbia Assistant Professor of Pediatrics, Drexel Candida Species, Aspergillus Species;
Management of HIV Infection University College of Medicine; Section of Antifungal Agents
Infectious Diseases, St. Christopher’s Hospital
Jane D. Siegel, MD for Children, Philadelphia, Pennsylvania Christen Rune Stensvold, BMedSc, MSc,
Public Health Medical Officer III, Healthcare Other Haemophilus Species and Aggregatibacter PhD
Associated Infections Program, California Species Senior Scientist, Department of Bacteria,
Department of Public Health, Richmond, Parasites, and Fungi, Statens Serum Institut,
California Paul Spearman, MD Copenhagen, Denmark
Pediatric Healthcare: Infection Epidemiology, Albert B. Sabin Professor, Department of Balantioides coli (Formerly Balantidium coli);
Prevention and Control, and Antimicrobial Pediatrics, University of Cincinnati College Blastocystis Species; Endolimax nana
Stewardship of Medicine; Director, Division of Infectious
Diseases, Cincinnati Children’s Hospital Erin K. Stokes, MPH
Robert David Siegel, MD, PhD Medical Center, Cincinnati, Ohio Surveillance Epidemiologist, Division of
Professor of Microbiology and Immunology, Acute Pneumonia and Its Complications Foodborne, Waterborne, and Environmental
Stanford University School of Medicine, Diseases, National Center for Emerging and
Stanford, California Joseph W. St. Geme III, MD Zoonotic Infectious Diseases, Centers for
Classification of Human Viruses Professor of Pediatrics and Microbiology, Disease Control and Prevention, Atlanta,
Perelman School of Medicine at the University Georgia
Kari A. Simonsen, MD of Pennsylvania; Chairman, Department of Other Vibrio Species
Professor of Pediatrics, Division of Infectious Pediatrics, Children’s Hospital of Philadelphia
Diseases, University of Nebraska Medical and University of Pennsylvania; Physician-in- Bradley P. Stoner, MD, PhD
Center, Omaha, Nebraska Chief, Department of Pediatrics, Children’s Professor and Head, Department of Public
Infectious Complications of Corticosteroid Hospital of Philadelphia, Philadelphia, Health Sciences, Queen’s University, Kingston,
Therapy Pennsylvania Ontario, Canada
Classification of Bacteria; Classification of Klebsiella granulomatis: Granuloma Inguinale
Upinder Singh, MD Streptococci; Enterococcus Species; Viridans (Donovanosis)
Professor and Division Chief, Division of Streptococci, Abiotrophia and Granulicatella
Infectious Diseases and Geographic Medicine, Species, and Streptococcus bovis Group; Gregory A. Storch, AB, MD
Department of Medicine, Stanford University Groups C and G Streptococci; Other Gram- Ruth L. Siteman Professor of Pediatrics,
School of Medicine, Stanford, California Positive, Catalase-Negative Cocci: Leuconostoc Washington University School of Medicine, St.
Entamoeba histolytica (Amebiasis); Other and Pediococcus Species and Other Genera; Louis, Missouri
Entamoeba, Amebae, and Intestinal Haemophilus influenzae Use of Common Clinical Laboratory Tests to
Flagellates; Naegleria fowleri; Acanthamoeba Assess Infectious and Inflammatory Diseases
Species Mary Allen Staat, MD, MPH
Professor of Pediatrics, University of Cincinnati Anne Straily, DVM, MPH, DACVPM
Christiana Smith, MD, MSCS College of Medicine; Director, International Parasitic Diseases Branch, Division of Parasitic
Assistant Professor of Pediatrics, University Adoption Center, Cincinnati Children’s Diseases and Malaria, Centers for Disease
of Colorado School of Medicine; Section Hospital Medical Center, Cincinnati, Ohio Control and Prevention, Atlanta, Georgia
of Infectious Diseases, Children’s Hospital Infectious Diseases in Refugee and Blood Trematodes: Schistosomiasis
Colorado, Aurora, Colorado Internationally Adopted Children
Pneumonia in the Immunocompromised Host; Kathleen E. Sullivan, MD, PhD
Diagnosis and Clinical Manifestations of HIV J. Erin Staples, MD, PhD Professor of Pediatrics, Perelman School of
Infection Lead, Surveillance and Epidemiology Team, Medicine at the University of Pennsylvania;
Arboviral Diseases Branch, Centers for Disease Chief, Division of Allergy and Immunology,
Control and Prevention, Fort Collins, Colorado The Children’s Hospital of Philadelphia,
Coltivirus (Colorado Tick Fever); Togaviridae: Philadelphia, Pennsylvania
Alphaviruses; Bunyaviruses Infectious Complications of Complement
Deficiency and Diseases of Its Dysregulation

xix
 Contributors

Douglas S. Swanson, MD Isaac Thomsen, MD, MSCI Russell B. Van Dvke, MD

Associate Professor of Pediatrics, University of Associate Professor–Pediatric Infectious Professor of Pediatrics, Tulane University
Missouri at Kansas City School of Medicine; Diseases, Vanderbilt University Medical School of Medicine, New Orleans, Louisiana
Division of Infectious Diseases, Children’s Center, Nashville, Tennessee Infectious Complications of HIV Infection
Mercy–Kansas City, Kansas City, Missouri Staphylococcus aureus
Chronic Meningitis Louise Elaine Vaz, MD, MPH
Richard B. Thomson, Jr., PhD, D(ABMM) Associate Professor of Pediatrics, Oregon
Robert R. Tanz, MD Clinical Professor of Pathology, The University Health & Sciences University; Division of
Professor Emeritus of Pediatrics, Division of of Chicago Pritzker School of Medicine; Infectious Diseases, Doernbecher Children’s
Advanced General Pediatrics & Primary Care, Medical Microbiologist, Department Hospital, Portland, Oregon
Northwestern University Feinberg School of of Pathology and Laboratory Medicine, The Systemic Inflammatory Response
Medicine, Ann & Robert H. Lurie Children’s NorthShore University HealthSystem, Syndrome, Sepsis, and Septic Shock
Hospital of Chicago, Chicago, Illinois Evanston, Illinois
Streptococcus pyogenes (Group A Streptococcus) Nocardia Species Vini Vijayan, MD
Pediatric Infectious Diseases Specialist,
Gillian Taormina, DO, MS Emily A. Thorell, MD, MSCI Division of Infectious Diseases, Valley
Assistant Professor of Pediatrics, Albany Associate Professor of Pediatrics, University Children’s Hospital, Madera, California
Medical College; Attending Physician, Division of Utah School of Medicine; Director, Bartonella Species (Cat-Scratch Disease)
of Pediatric Infectious Diseases, Albany Antimicrobial Stewardship Program, Associate
Medical Center, Albany, New York Hospital Epidemiologist, Division of Infectious Jennifer Vodzak, MD
Intra-abdominal, Visceral, and Retroperitoneal Diseases, Primary Children’s Medical Center, Assistant Professor of Pediatrics, Geisinger
Abscesses Salt Lake City, Utah Commonwealth School of Medicine, Scranton,
Cervical Lymphadenitis and Neck Infections Pennsylvania; Director, Division of Infectious
Jacqueline E. Tate, PhD Diseases and Director, Pediatric Quality,
Epidemiologist, Division of Viral Diseases, Vivian Tien, MD Safety and Best Practice, Geisinger Janet Weis
Centers for Disease Control and Prevention, Fellow, Division of Infectious Diseases Children’s Hospital, Danville, Pennsylvania
Atlanta, Georgia and Geographic Medicine, Department of Other Haemophilus Species and Aggregatibacter
Astroviruses Medicine, Stanford University School of Species; Fusobacterium Species; Use of
Medicine, Stanford, California Common Clinical Laboratory Tests to Assess
Jeanette Taveras, DO Entamoeba histolytica (Amebiasis); Other Infectious and Inflammatory Diseases
Assistant Professor of Pediatrics, Drexel Entamoeba, Amebae, and Intestinal Flagellates;
University College of Medicine; Section of Naegleria fowleri; Acanthamoeba Species Thor A. Wagner, MD
Infectious Diseases, St. Christopher’s Hospital Associate Professor of Pediatrics, University
for Children, Philadelphia, Pennsylvania Nicole H. Tobin, MD of Washington, Center for Global Infectious
Fever and the Inflammatory Response Associate Adjunct Professor, Department of Diseases Research, Seattle Children’s Research
Pediatrics, David Geffen School of Medicine Institute, Seattle, Washington
Marc Tebruegge, DTM&H, MRCPCH, MSc, at the University of California, Los Angeles; Introduction to Retroviridae; Human
MD, PhD Attending Physician, Division of Infectious T-Cell Lymphotropic Viruses; Human
Clinical Senior Lecturer, Department of Diseases, UCLA Mattel Children’s Hospital, Immunodeficiency Virus
Paediatrics, The University of Melbourne, Los Angeles, California
Parkville, Victoria, Australia; Honorary Immunopathogenesis of HIV-1 Infection Ellen R. Wald, MD
Associate Professor, Department of Infection, Alfred Dorrance Daniels Professor of Diseases
Immunity, and Inflammation, UCL Great Philip Toltzis, MD of Children, Chair, Department of Pediatrics,
Ormond Street Institute of Child Health, Professor of Pediatrics, Case Western Reserve University of Wisconsin School of Medicine
London, United Kingdom University School of Medicine; Infectious & Public Health; Pediatrician-in-Chief,
Infections Related to the Upper and Middle Diseases Specialist, Division of Pediatric Department of Pediatrics, American Family
Airways; Mycobacterium Nontuberculosis Pharmacology and Critical Care, Rainbow Children’s Hospital, Madison, Wisconsin
Species Babies and Children’s Hospital, Cleveland, Mastoiditis; Sinusitis; Preseptal and Orbital
Ohio Infections
Eyasu H. Teshale, MD Coagulase-Negative Staphylococci and
Medical Officer, Division of Viral Hepatitis, Micrococcaceae Rebecca Wallihan, MD
Centers for Disease Control and Prevention, Attending Physician, Division of Infectious
Atlanta, Georgia James Treat, MD Diseases, Nationwide Children’s Hospital and
Hepatitis C Virus; Hepatitis E Virus Professor of Pediatrics, Perelman School of The Ohio State University College of Medicine,
Medicine at the University of Pennsylvania; Columbus, Ohio
George R. Thompson III, MD Fellowship Director, Education Director and Less Commonly Encountered Enterobacterales
Professor of Medicine, Division of Infectious Attending Physician, Pediatric Dermatology,
Diseases, UC Davis Medical Center, Children’s Hospital of Philadelphia, Huanyu Wang, PhD, DABMM
Sacramento, California Philadelphia, Pennsylvania Assistant Professor of Pathology and
Cryptococcus Species; Coccidioides immitis and Vesicles and Bullae Laboratory Medicine, The Ohio State
Coccidioides posadasii (Coccidioidomycosis) University College of Medicine; Assistant
Stephanie B. Troy, MD Director, Clinical Microbiology and
Robert Thompson-Stone, MD Medical Officer, Division of Antivirals, Office Immunoserology Laboratories, Nationwide
Associate Professor of Neurology and of Infectious Diseases/Office of New Drugs, Children’s Hospital, Columbus, Ohio
Pediatrics, University of Rochester School Center for Drug Evaluation and Research, US Proteus, Providencia, and Morganella Species;
of Medicine & Dentistry; Division of Child Food and Drug Administration, Silver Spring, Serratia Species; Acinetobacter Species
Neurology, Golisano Children’s Hospital, Maryland
University of Rochester Medical Center, Polioviruses
Rochester, New York
Neurologic Syndromes

xx
 Contributors

Zoon Wangu, MD Cydni Williams, MD, MCR Huan Xu, MD

Assistant Professor of Pediatrics–Infectious Associate Professor of Pediatrics, Oregon Assistant Professor of Medicine, Baylor College
Diseases and Immunology, UMass Chan Health & Science University; Director, of Medicine; Division of Infectious Diseases,
Medical School, UMass Memorial Children’s Pediatric Critical Care and Neurotrauma Michael E. Debakey Veteran’s Administration
Medical Center, Worcester, Massachusetts; Recovery Program, OHSU Doernbecher Medical Center, Houston, Texas
Clinical Faculty, Ratelle STD/HIV Prevention Children’s Hospital, Portland, Oregon Taenia solium, Taenia asiatica, and Taenia
Training Center, Massachusetts Department of The Systemic Inflammatory Response saginata: Taeniasis and Cysticercosis; Taenia
Public Health, Jamaica Plain, Massachusetts Syndrome, Sepsis, and Septic Shock (Multiceps) multiceps and Taenia serialis:
Protection of Travelers; Neisseria gonorrhoeae; Coenurosis
Other Neisseria Species John V. Williams, MD
Henry L. Hillman Professor of Pediatrics, Pablo Yagupsky, MD
Matthew Washam, MD, MPH Microbiology & Molecular Genetics, Professor of Pediatrics and Clinical
Assistant Professor of Pediatrics, The Ohio University of Pittsburgh School of Medicine; Microbiology, Director, The Joyce and Irving
State University College of Medicine; Division Chief, Pediatric Infectious Diseases, UPMC Goldman Medical School, Ben-Gurion
of Infectious Diseases, Nationwide Children’s Children’s Hospital of Pittsburgh, Pittsburgh, University of the Negev; Director, The Clinical
Hospital, Columbus, Ohio Pennsylvania Microbiology Laboratory, Soroka University
Klebsiella and Raoultella Species Human Metapneumovirus Medical Center, Beer-Sheva, Israel
Kingella Species
Valerie Waters, MD, MSc Rodney E. Willoughby, Jr., MD
Professor of Paediatric Infectious Diseases, Professor of Pediatrics, Medical College of Jumi Yi, MD
Senior Associate Scientist, Research Institute, Wisconsin, Milwaukee, Wisconsin Director, Global Regulatory Affairs and Clinical
The Hospital for Sick Children, Toronto, Rabies Virus Safety, Merck & Co., Rahway, New Jersey
Ontario, Canada Approach to the Diagnosis and Management
Pseudomonas Species and Related Organisms; Robert R. Wittler, MD of Gastrointestinal Tract Infections;
Burkholderia cepacia Complex and Other Professor of Pediatrics, Kansas University Campylobacter jejuni and Campylobacter coli
Burkholderia Species; Stenotrophomonas School of Medicine—Wichita, Wichita, Kansas
maltophilia Persistent and Recurrent Pneumonia Jonathan Yoder, MSW, MPH
Epidemiologist, Division of Foodborne,
Joshua R. Watson, MD James B. Wood, MD, MSCI Waterborne, and Environmental Diseases,
The Ohio State University College of Medicine; Assistant Professor of Pediatrics, Indiana Centers for Disease Control and Prevention,
Attending Physician, Division of Infectious University School of Medicine; Ryan White Atlanta, Georgia
Diseases, Nationwide Children’s Hospital, Center for Pediatric Infectious Diseases Enteric Diseases Transmitted Through Food,
Columbus, Ohio and Global Health, Division of Pediatric & Water, and Zoonotic Exposures
Less Commonly Encountered Enterobacterales Adolescent Clinical Effectiveness Research, Riley
Hospital for Children, Indianapolis, Indiana †Edward J. Young, MD
Jill E. Weatherhead, MD, PhD Musculoskeletal Symptom Complexes; Professor of Medicine, Baylor College of
Director of Medical Education, National Histoplasma capsulatum (Histoplasmosis) Medicine; Michael E. DeBakey Veteran’s
School of Tropical Medicine, Assistant Administration Medical Center, Houston, Texas
Professor of Infectious Diseases and Pediatric Charles Reece Woods, MD Brucella Species (Brucellosis)
Tropical Medicine, Baylor College of Medicine, Professor and Chair, Department of Pediatrics,
Houston, Texas University of Tennessee College of Medicine Andrea L. Zaenglein, MD
Classification of Parasites; Intestinal Nematodes Chattanooga; Chief Executive Officer, Professor of Dermatology and Pediatrics,
Children’s Hospital, Erlanger Health System, Penn State University; Attending Physician
Geoffrey A. Weinberg, MD Chattanooga, Tennessee in Dermatology, Hershey Medical Center,
Professor of Pediatrics, University of Rochester Subcutaneous Tissue Infections and Abscesses Penn State Children’s Hospital, Hershey,
School of Medicine & Dentistry; Director, Pennsylvania
Clinical Pediatric Infectious Diseases & Kimberly A. Workowski, MD Erythematous Macules and Papules
Pediatric HIV Program, Golisano Children’s Professor of Medicine and Infectious Diseases,
Hospital, University of Rochester Medical Emory University School of Medicine; Clinical Petra Zimmermann, MD, PhD
Center, Rochester, New York Consultant, Epidemiology and Surveillance Consultant in Paediatric Infectious Diseases
Neurologic Syndromes Branch, Division of STD Prevention, Centers and Senior Lecturer, Faculty of Science and
for Disease Control and Prevention, Atlanta, Medicine, University of Fribourg, Fribourg,
Mark K. Weng, MD, MSc Georgia Switzerland; Honorary Fellow, Infectious
Medical Epidemiologist, Division of Viral Genitourinary Skin and Mucous Membrane Diseases Research Group, Murdoch Children’s
Hepatitis, Centers for Disease Control and Infections and Inguinal Lymphadenopathy; Research Institute Melbourne, Parkville,
Prevention, Atlanta, Georgia Trichomonas vaginalis Victoria, Australia
Hepatitis A Virus Infections Related to the Upper and Middle
Terry W. Wright, PhD Airways
Nathan P. Wiederhold, PharmD Associate Professor of Pediatrics, University of
Professor of Pathology and Laboratory Rochester School of Medicine and Dentistry, Wenjing Zong, MD
Medicine, Director, Fungus Testing Rochester, New York Instructor of Pediatrics, Perelman School of
Laboratory, UT Health San Antonio, San Pneumocystis jirovecii Medicine at the University of Pennsylvania;
Antonio, Texas Attending Physician, Division of Pediatric
Classification of Fungi; Agents of Hsi-Yang Wu, MD Gastroenterology, Hepatology, and Nutrition,
Hyalohyphomycosis and Phaeohyphomycosis; Director of Pediatric Urology; Warren The Children’s Hospital of Philadelphia,
Agents of Mucormycosis; Malassezia Species; Alpert Medical School of Brown University, Philadelphia, Pennsylvania
Sporothrix schenckii Complex (Sporotrichosis) Providence, Rhode Island Anaerobic Bacteria: Clinical Concepts and the
Urinary Tract Infections, Renal Abscess, and Microbiome in Health and Disease
Harold C. Wiesenfeld, MD, CM Other Complex Renal Infections
Professor of Obstetrics, Gynecology, and
Reproductive Sciences, University of Pittsburgh
School of Medicine, Pittsburgh, Pennsylvania
Pelvic Inflammatory Disease †Deceased.

xxi
 PART Understanding, Controlling, and Preventing Infectious Diseases
I
SECTION A: Epidemiology and Control of Infectious Diseases

1 Principles of Epidemiology and Public Health

Lucy A. McNamara and Stacey W. Martin

Epidemiology is the study of the distribution and determinants of disease Case Definition
or other health-related states or events in specified populations and the
application of this study to the control of health problems.1 A key com- Establishing a standard case definition is a necessary first step for sur-
ponent of this definition is that epidemiology focuses on populations, veillance and description of the epidemiology of a disease or health
an emphasis that distinguishes epidemiology from clinical case studies, event.2 Formulation of a case definition is particularly important when
which focus on individual subjects. laboratory diagnostic testing results are not definitive. More restric-
Health events can be characterized by their distribution (descriptive tive case definitions have greater specificity and minimize misclassi-
epidemiology) and by factors that influence their occurrence (analytic fication of persons without the condition of interest as cases; however,
epidemiology). In both descriptive and analytic epidemiology, health- they can exclude true cases and may be most useful when investigating
related questions are addressed using quantitative methods to identify a newly recognized condition, in which the ability to determine etiol-
patterns or associations from which inferences can be drawn and inter- ogy, pathogenesis, or risk factors is decreased by inclusion of noncases
ventions developed, applied, and assessed. in the study population. A more inclusive definition can be important
in an outbreak setting to increase sensitivity to detect potential cases
for further investigation or to inform application of preventive inter-
DESCRIPTIVE EPIDEMIOLOGY ventions (e.g., reactive vaccination campaigns). Multiple research or
public health objectives can be addressed by developing a tiered case
Surveillance definition that incorporates varying degrees of diagnostic certainty for
The goals of descriptive epidemiology are to define the frequency of confirmed, probable, and suspected cases. The Council of State and Ter-
health-related events and determine their distribution by person, place, ritorial Epidemiologists (CSTE) provides uniform surveillance case defi-
and time. The foundation of descriptive epidemiology is surveillance, or nitions for nationally notifiable infectious and noninfectious conditions
case detection. Retrospective surveillance identifies health events from (https://wwwn.cdc.gov/nndss/case-definitions.html).
existing data, such as clinical or laboratory records, hospital discharge
data, and death certificates. Prospective surveillance identifies and col- Sensitivity, Specificity, and Predictive Value
lects information about cases as they occur, for example, through ongoing
laboratory-based reporting. Sensitivity, specificity, and predictive values can be used to quantify the
With passive surveillance, case reports are supplied voluntarily by clini- performance of a case definition or the results of a diagnostic test or algo-
cians, laboratories, health departments, or other sources. The complete- rithm (Table 1.1). Sensitivity and specificity are intrinsic measures of a
ness and accuracy of passive reporting are affected by whether reporting case definition or diagnostic test, whereas predictive values vary with the
is legally mandated, the ease of establishing a definitive diagnosis for the prevalence of a condition within a population. Even with a highly specific
disease under surveillance, illness severity, interest in and awareness of diagnostic test, if a disease is uncommon among the people tested, a large
the medical condition among the public and the medical community, and proportion of positive test results will be false positives, and the positive
by whether a report will elicit a public health response. Because more predictive value will be low (Table 1.2). If the test is applied more selec-
severe illness is more likely to be diagnosed and reported, the severity tively, such that the proportion of people tested who truly have disease
and clinical spectrum of passively reported cases often differ from those is greater, the test’s predictive value will be improved. Thus, predictive
of all cases of an illness. Weekly and annual state counts of passively values depend both on test sensitivity and specificity, and on the disease
collected reports of nationally notifiable diseases are available on the prevalence in the population in which the test is applied, also called the
National Notifiable Diseases System (NNDSS) Data and Statistics web pre-test probability.
page (https://wwwn.cdc.gov/nndss/data-and-statistics.html). Often, the sensitivity and specificity of a test are inversely related.
In active surveillance, an effort is made to ascertain all cases of a condi- Selecting the optimal balance of sensitivity and specificity depends on the
tion occurring in a defined population. Active case finding can be pro- purpose for which the test is used. Generally, a screening test should be
spective (through routine contacts with reporting sources), retrospective highly sensitive, whereas a follow-up confirmatory test should be highly
(through record audit), or both. Population-based active surveillance, in specific.
which all cases in a defined geographic area are identified and reported,
provides the most complete and unbiased ascertainment of disease and is Incidence and Prevalence
optimal for describing the rate of a disease and its clinical spectrum. By
contrast, active surveillance conducted at only one or several participat- Characterizing disease frequency is one of the most important aspects of
ing facilities, often referred to as sentinel surveillance, can yield biased descriptive epidemiology. Frequency measures typically include a count
information on disease frequency or spectrum based on the representa- of new or existing cases of disease as the numerator and a quantifica-
tiveness of the patient population and the size of the sample obtained. The tion of the population at risk as the denominator. Cumulative incidence
range and severity of clinical symptoms also influence whether active sur- is expressed as a proportion and describes the number of new cases of
veillance is able to ascertain all cases of a disease; individuals with mild an illness occurring in a fixed at-risk population over a specified period
disease may not present to a physician for diagnosis. of time. The incidence density or incidence rate is the rate of new cases

1
 PART I Understanding, Controlling, and Preventing Infectious Diseases
SECTION A Epidemiology and Control of Infectious Diseases

TABLE 1.1   Definitions and Formulas for the Calculation of Important Epidemiologic Parameters
Measures of test Sensitivity: Proportion of true positive (diseased) with a A/(A + C)
accuracy positive test result
Specificity: Proportion of true negative (nondiseased) with a D/(B + D)
negative test result
Positive predictive value (PPV): Proportion of positive test A/(A + B)
results that are true positives
Negative predictive value (NPV): Proportion of negative test D/(C + D)
results that are true negatives
Measures of data Variance: Statistic describing variability among individual [1 (n − 1)][ x1 − x )2 +
dispersion and members of a population ( x 2 − x )2 + … + ( x n − x )2 ]
precision
Standard deviation (SD): A second, more commonly used Variance
statistic describing variability among individual members
of a population
Standard error (SE): Statistic describing the variability SD
of sample-based point estimates (P) around the true
√n
population value being estimated
Confidence interval: A range of values that is believed to —
contain the true value within a defined level of certainty
(usually 95%)

Presumed index case

TABLE 1.2   Positive and Negative Predictive Values for a Hypothetical Case
Diagnostic Test Having a Sensitivity of 90% and a Specificity of 90% Food handler case
Number of cases

10 Secondary case
Proportion With Positive Predictive Negative Predictive
Condition Value Value
1% 8% >99%
5
10% 50% 99%
20% 69% 97%
50% 90% 90%
1 7 13 19 25 31 6 12 18 24 30 6 12 18 24
October November December
of disease in a dynamic at-risk population; the denominator typically is Date of onset
expressed as the population-time at-risk (e.g., person-time). FIGURE 1.1. Example of an epidemic curve for a common source outbreak
Because the occurrence of many infections varies with season, extrap- with continuous exposure. Cases of hepatitis A by date of onset in Fayetteville,
olating annual incidence from cases detected during a short observation Arkansas, from November to December 1979. (From Centers for Disease Control
period can be inaccurate. In describing the risk of acquiring illness dur- and Prevention, unpublished data.)
ing a disease outbreak, the attack rate, defined as the number of new cases
of disease occurring in a specified population and time period, is a useful
measure. Finally, the case-fatality rate, or proportion of cases of a disease the impact of prevention programs. The timing of illness in outbreaks can
that result in death, is used to quantify the mortality resulting from a be displayed in an epidemic curve (Fig. 1.1) and can be useful in defin-
disease in a particular population and time period. ing the mode of transmission or incubation period, or for assessing the
Prevalence refers to the proportion of the population having a con- effectiveness of control measures.
dition at a specific point in time. As such, it is a better measure of
disease burden for chronic conditions than is incidence or attack rate, ANALYTIC EPIDEMIOLOGY
which identify only new (incident) cases. Prevalent cases of disease
can be ascertained in a cross-sectional survey, whereas determining Study Design
incidence requires longitudinal surveillance. When disease prevalence
(P) is low and incidence (I) and duration (D) are stable, prevalence The goal of analytic epidemiologic studies is to assess for and quantify
is a function of disease incidence multiplied by its average duration the association between an exposure and a health outcome. This goal can
(P = I × D). be addressed in experimental or observational studies. In experimental
studies, hypotheses are tested by systematically allocating an exposure of
interest to subjects in separate groups to achieve the desired comparison.
Describing Illness by Person, Place, and Time Such studies include randomized, controlled, double-blind treatment
Characterizing disease by person, place, and time is often useful. Demo- trials as well as laboratory experiments. By carefully controlling study
graphic variables, including age, sex, socioeconomic status, and race or variables, investigators can restrict differences among groups and thereby
ethnicity, often are associated with the risk of disease. Describing a dis- increase the likelihood that the observed differences are a consequence
ease by place can help define risk groups, for example, when an illness is of the specific factor being studied. Because experiments are prospective,
caused by an environmental exposure or is vector borne, or during an the temporal sequence of exposure and outcome can be established, mak-
outbreak with a point source exposure. Time also is a useful descriptor of ing it possible to define cause and effect.
disease occurrence. Evaluating long-term (secular) trends provides infor- By contrast, observational studies test hypotheses using observational
mation that can be used to identify emerging health problems or to assess methods to assess exposures and outcomes among individual subjects in

2
 Principles of Epidemiology and Public Health 1
TABLE 1.3   Types of Observational Studies and Their Advantages and Disadvantages
Type of Study Design and Characteristics Advantages Disadvantages
Cohort Prospective or retrospective Ideal for outbreak investigations in defined Unsuited for rare diseases or those with
populations long latency
Select study group Prospective design ensures that exposure Expensive
preceded disease
Observe for exposures and disease Selection of study group is unbiased by Can require long follow-up periods
knowledge of disease status
Outcome measures used: Relative risk (RR) or RR and HR accurately describe risk given Difficult to investigate multiple exposures
hazard ratio (HR) of disease given exposure an exposure
Cross-sectional Nondirectional Rapid, easy to perform, and inexpensive Timing of exposure and disease can be
difficult to determine
Select study group Ideal to determine knowledge, attitudes, Biases can affect recall of past exposures
and behaviors
Determine exposure and disease status
Outcome measures used: Prevalence ratio for
disease given exposure
Case-control Retrospective Rapid, easy to perform, and inexpensive Timing of exposure and disease can be
difficult to determine
Identify cases with disease Ideal for studying rare diseases, those with Biases can occur in selecting cases and
long latency, new diseases controls and determining exposures
Identify controls without disease OR only provides an estimate of the RR if
disease is rare
Determine exposures in cases and controls
Outcome measures used: Odds ratio (OR) for
an exposure given disease

populations and to identify statistical associations from which inferences an exposure. However, in a cohort study it can be difficult to investigate
regarding causation are drawn. Although observational studies can- multiple exposures as risk factors for a single outcome. Cohort studies
not be controlled to the same degree as experiments, they are practical also are impractical for studying rare diseases or conditions with a long
in circumstances in which exposures or behaviors cannot be assigned. latent period between exposure and the onset of clinical illness. In gen-
Moreover, the results often are more generalizable to a real population eral, cohort studies are unsuited for investigating risk factors for new or
having a wide range of attributes. The 3 basic types of observational stud- rare diseases or for generating new hypotheses about possible exposure-
ies are cohort studies, cross-sectional studies, and case-control studies disease relationships.
(Table 1.3). Hybrid study designs, incorporating components of these 3 Cohort studies provide data not only on whether an outcome occurs
types, also have been developed.3 In planning observational studies, care but also, for those experiencing the outcome, on when it occurs. Analysis
must be taken in the selection of participants to minimize the possibility of time-to-event data for outcomes such as death or illness is a power-
of bias. Selection bias results when study subjects have differing prob- ful approach to assess or compare the impacts of preventive or therapeu-
abilities of being selected and the probability of selection is related to the tic interventions. The probability of remaining event-free over time can
risk factors or outcomes under evaluation. be expressed in a survival curve where the event-free probability is ini-
In contrast to experimental or observational studies that analyze infor- tially 1 and declines in a step-function as the outcomes of interest occur
mation about individual subjects, ecologic studies draw inferences from (Fig. 1.2A). Time-to-event data also can be displayed as the cumulative
data on a population level. Causal inferences from ecologic studies must hazard of an event occurring among members of a cohort that increases
be made with caution because relationships observed on a population from 0 at enrollment (Fig. 1.2B). These 2 approaches are related in that
level do not necessarily apply on the individual level (a problem known the hazard reflects the incident event rate, whereas survival reflects the
as the ecologic fallacy). Because of these drawbacks, ecologic studies are cumulative nonoccurrence of that outcome.4,5 With time-to-event analy-
suited best for generating hypotheses that can be tested using other study sis, the association between exposure and disease often is expressed as a
methods. hazard ratio. Like relative risk, the hazard ratio is a comparative measure
of risk between exposed and unexposed groups. The primary difference
Cohort Studies is that the hazard ratio compares event experience over the entire time
period, whereas the relative risk compares cumulative event occurrence
In a cohort study, subjects are categorized based on their exposure to a at the study endpoint.6
suspected risk factor and are observed for the development of disease or
other health-related outcome. Associations between exposure and dis- Cross-Sectional Studies
ease are expressed by the relative risk of disease, or risk ratio, in exposed
and unexposed groups (Table 1.4). Cohort studies typically are pro- In a cross-sectional study, or survey, a sample is selected, and at a single
spective, with exposure defined before disease occurs. However, cohort point in time exposures and outcome are determined. Outcomes can
studies also can be retrospective, in which the cohort is selected after include disease status or behaviors and beliefs, and multiple exposures
the outcome has occurred. In this case, exposures are determined from can be evaluated as explanations for the outcome. Associations are char-
existing records that preceded the outcome, and thus the directional- acterized by the prevalence ratio, similar to the risk ratio in cohort stud-
ity of the exposure-disease relationship is still forward. Characterizing ies. Because neither exposures nor outcomes are used in selection of the
exposures before development of disease is a major benefit of cohort study group, prevalence is an estimate of that in the overall population
studies because this approach minimizes selection bias and simplifies from which the sample was drawn. National survey data characterizing
inference of cause and effect. Another advantage of cohort studies is that health status, behaviors, and medical care are available from the National
they can be used to assess multiple potential outcomes resulting from Center for Health Statistics (http://www.cdc.gov/nchs/index.htm).

3
 PART I Understanding, Controlling, and Preventing Infectious Diseases
SECTION A Epidemiology and Control of Infectious Diseases

TABLE 1.4   Measures of Association, Risk, and Impact

Absolute measures of Absolute risk reduction (ARR), excess risk, or at- (A/(A + B)) − (C/(C + D))
association and risk tributable risk: Difference in the incidence of the
outcome between exposed and unexposed
Number needed to treat (NNT): Number of indi- 1/ARR
vidual subjects who must receive an intervention
(or exposure) to prevent one negative outcome
Relative measures of Relative risk or risk ratio (RR): Risk (probability) of A ( A + B)
association and risk a health event in those with a given exposure C ( C + D)
divided by the risk in those without the exposure
Odds ratio (OR): Odds of a given exposure among AD/BC
those with a health event divided by odds of
exposure among those without the health event
Measure of impact Population attributable fraction: The proportion [Pe (RR − 1)]/[1 + Pe (RR − 1)]
of disease in a population that results from the [­Proportion exposed, Pe = (A + B)/
specific exposure (A + B + C + D)]
Vaccine efficacy/effectiveness (VE): The percentage (1 − RR) × 100
reduction in incidence of a disease among per- or
sons who have received a vaccine compared with (1 − OR) × 100
the incidence in persons who have not received
the vaccine

Case-Control Studies hospital-based studies, differential referral also can bias selection of a
study sample. This bias would occur if, for example, the frequency of an
In a case-control study, the investigator identifies a group of people with a exposure varied with socioeconomic status and a hospital predominantly
disease or outcome of interest (cases) and compares their exposures with admitted persons from either a high-income group or a low-income
those in a selected group of people who do not have disease (controls). group. Bias also can occur when eligible subjects refuse to participate in
Differences between the groups are expressed by an odds ratio, which a study.
compares the odds of an exposure in case and control groups (Table 1.4). Determination of exposures can also be affected by several types of
The odds ratio is not the same as a risk ratio; however, it provides an bias. Recall of exposures can be different for persons who have had an
estimate of the risk ratio if the disease or outcome in question is rare. illness compared with people who were well. This bias occurs in either
Case-control studies are retrospective in that disease status is known and direction: patients may be more likely to remember an exposure that
serves as the basis for selecting the 2 comparison groups; exposures are they associate with their illness (e.g., what was eaten before an episode
then determined by reviewing available records or by interview. of diarrhea) or less likely to recall an exposure if a severe illness affected
A major advantage of case-control studies is their efficiency in study- memory. Interviewers can introduce bias by questioning cases and con-
ing uncommon diseases or diseases with a long latency. Case-control trols differently about their exposures. Misclassification of exposures can
studies also can evaluate multiple exposures that may contribute to a also result from errors in measurement such as can occur with the use of
single outcome; study subjects frequently can be identified from existing an inaccurate laboratory test. Although systematic misclassification can
sources (e.g., hospital or laboratory records, disease registries, or surveil- result in bias, misclassification of exposure often is random rather than
lance reports), and after identification of suitable control subjects, data systematic.
on previous exposures can be collected rapidly. Case-control studies also Even a carefully designed study that minimizes potential biases can
have several drawbacks. Bias can be introduced during selection of cases lead to erroneous causal inferences. An exposure can falsely appear to be
and controls and in determining exposures retrospectively, and inferring associated with disease because it is closely linked to the true, but unde-
causation from statistically significant associations can in some situations termined, risk factor. For example, race often is found to be associated
be complicated by difficulty in determining the temporal sequence of with the risk of a disease, but in many instances the true risk factor is
exposure and disease. likely an unmeasured variable that is associated with race, such as socio-
economic status. The risk of making incorrect inferences can be mini-
Causal Inference and the Impact of Bias mized by considering certain general criteria for establishing causation.
These criteria include the strength of an association, the presence of a
The impact of potential bias is particularly important in observational dose-response effect, a clear temporal sequence of exposure to disease,
studies. The validity of a study is the degree to which inferences drawn the consistency of findings with those of other studies, and the biologic
from a study are warranted. Internal validity refers to the correctness of plausibility of the hypothesis.8
study conclusions for the population from which the study sample was
drawn, whereas external validity refers to the extent to which the study
results can be generalized beyond the population sampled. The validity of
Statistical Analysis
a study can be affected by bias, or systematic error, in selecting the study
participants (sampling), in ascertaining their exposures, or in analyzing
Characteristics of Populations and Samples
and interpreting study data. For errors to result in bias, they must be sys- While epidemiologic analysis seeks to draw valid conclusions about popu-
tematic, or directional. Nonsystematic error (random misclassification) lations, the entire population rarely is included in a study. An assumption
decreases the ability of a study to identify a true association but does not underlying statistical analysis is that the sample evaluated was selected
usually result in detection of a spurious association. randomly from the population. Often, this criterion is not met and calls
Several sources of bias can occur in selection of study participants into question the appropriateness and interpretation of statistical analyses.
(Box 1.1).7 Diagnosis bias results when persons with a given exposure are The mean, median, and mode describe central values for samples and
more likely to be diagnosed as having disease than are people without populations. The arithmetic mean is the average, determined by sum-
the exposure (or vice versa); this can occur because diagnostic testing ming individual values and dividing by the sample size. When data are
is more or less likely to be done based on exposure or because the inter- not normally distributed, or skewed, calculation of a geometric mean can
pretation of a test may be affected by knowledge of exposure status. For limit the impact of outlying values. The geometric mean is calculated by

4
 Principles of Epidemiology and Public Health 1
1.0
BOX 1.1 Potential Sources of Bias in Observational Studiesa

0.8 BIAS IN CASE ASCERTAINMENT AND CASE/CONTROL

SELECTION
Probability of survival

• S urveillance bias: differential surveillance or reporting for exposed

0.6 and unexposed
• Diagnosis bias: differential use of diagnostic tests in exposed and
unexposed
0.4 • Referral bias: differential admission to hospital based on an expo-
sure or a variable associated with exposure
• Selection bias: differential sampling of cases based on an exposure
0.2 or a variable associated with exposure
• Nonresponse bias: differential outcome or exposures of respond-
ers and nonresponders
0.0 • Survival bias: differential exposures between those who survive to
0 7 14 21 28 35 be included in a study and those who die following an illness
Days post blood culture • Misclassification bias: systematic error in classification of disease
status
Combination therapy (n = 47) BIAS IN ESTIMATION OF EXPOSURE
$ Monotherapy (n = 47) • R ecall bias: differential recall of exposures based on disease
status
• Interviewer bias: differential ascertainment of exposures based on
disease status
0.4 • Misclassification bias: systematic errors in measurement or
­classification of exposure

0.3
Cumulative hazard

aA more complete listing is provided by Sackett.7

0.2
(Table 1.1). For a normally distributed population, 68% of values fall
within 1 standard deviation of the mean, and 95% of values fall within
0.1 1.96 standard deviations.
When analyzing a sample, the mean or other statistics describing the
sample represent a point estimate of that parameter for the entire popula-
0.0 tion. If another random sample were drawn from the same population,
the point estimate for the parameter of interest likely would be differ-
0 10 20 30 40 50 60
ent, depending on the variability in the population and the sample size
Age (months) selected. The standard error is used to describe the precision of a point
estimate (e.g., mean, odds ratio, relative risk) and depends on sample
HBV standard deviation and the sample size (Table 1.1).
% A confidence interval defines a range of values that includes the true
PncCRM
population value within a defined level of certainty. Most often, the 95%
FIGURE 1.2. Example of Kaplan-Meier and cumulative hazard curves. (A) confidence interval is presented (Table 1.1).
Survival plot for critically ill patients with Streptococcus pneumoniae bacteremia
treated with monotherapy or combination therapy. (B) Cumulative hazard of
tympanostomy tube placement from 2 months until 4–5 years of age in children Absolute and Relative Measures of Association
who received pneumococcal conjugate vaccine (PncCRM) or a control vaccine Measures of association are used to assess the strength of an association
(hepatitis B vaccine [HBV]). ([A] Redrawn from Baddour LM, Yu VL, Klugman KP,
between an exposure and an outcome. In a cohort study, the absolute risk
et al. Combination antibiotic therapy lowers mortality among severely ill patients
reduction (also known as excess risk, attributable risk, or risk difference)
with pneumococcal bacteremia. Am J Respir Crit Care Med. 2004;170:440–444.
is the difference in the incidence of the outcome between exposed and
[B] Redrawn from Palmu AAI, Verho J, Jokinen J, et al. The seven-valent
pneumococcal conjugate vaccine reduced tympanostomy tube placement in
unexposed subjects. The number needed to treat (NNT) is a measure of the
children. Pediatr Infect Dis J. 2004;23:732–738.) number of individual subjects who must receive a treatment to prevent a
single negative outcome and is calculated as the reciprocal of the absolute
risk reduction. In addition to absolute measures, relative measures also
are useful for describing the strength of an association. In a cohort study
taking the nth root of the product of all the individual values, where n is or survey, the relative risk or risk ratio compares the risk of disease for
the total number of individual values. For example, immunogenicity of subjects with versus subjects without an exposure (Table 1.4). In case-
vaccines is usually expressed by the geometric mean titer. The median, or control studies, association is assessed by the odds ratio, which compares
middle value, is another way to describe nonnormally distributed data. the odds of exposure among subjects with and without a disease or health
The mode, or most commonly occurring value in a sample, rarely is used. outcome; when disease is uncommon (<10%) in both exposed and unex-
Several measures can be used to describe the variability in a sample. posed groups, the odds ratio approximates the relative risk. For time-
The range describes the difference between the highest and lowest value, to-event analyses, the comparative risk is expressed as the hazard ratio.
whereas the interquartile range defines the difference between the 25th Odds ratios, relative risks, and hazard ratios >1 signify increased risk
and 75th percentiles. Variation among individual elements most often given exposure, and values <1 suggest that exposure decreases the risk
is characterized by the variance or standard deviation. The variance is of an outcome. Because observational studies generally do not include
the mean of the squared deviation of each observation from the sam- all members of a population, these measures of association represent an
ple’s mean. The standard deviation is the square root of the variance estimate of the true value within the entire population. Statistical analyses

5
 PART I Understanding, Controlling, and Preventing Infectious Diseases
SECTION A Epidemiology and Control of Infectious Diseases

can help guide investigators in making causal inferences based on point significant difference among treatment groups. However, only 3 of these
estimates of these measures of association. trials were adequately powered to exclude a 10% difference in mortality,
thus showing that many studies potentially missed a clinically significant
Statistical Significance difference.11
In some situations, an investigator would want to detect a significant
Statistical tests are applied to assess the likelihood that the study results difference among study groups as soon as possible, for example, when a
were obtained by chance alone rather than representing a true differ- therapeutic or preventive intervention could be applied once a risk group
ence within the population. Most investigators consider a P value <0.05 is identified or when concerns exist about the safety of a drug or vaccine.
as being statistically significant, indicating a <5% risk that the observed One approach to this situation is to include in the study design an interim
association is the result of chance alone (designated a type I error, the analysis after a specified number of subjects are evaluated. Because the
probability of which is the alpha level). Although use of this cutoff for likelihood of identifying chance differences as significant increases with
significance testing has become conventional, ignoring higher P values the number of analyses, it is recommended that the threshold for defining
can lead to missing a real and important association, whereas blind faith statistical significance should become more stringent as the number of
in the significance of lower P values can lead to erroneous conclusions. planned analyses increases.12 If each interim analysis can lead the inves-
Statistical testing should contribute to, but not replace, criteria for evalu- tigators to stop the trial, this study design is considered a group sequen-
ating possible causation. tial method.13 Another example of a group sequential design is when
Statistical significance also can be defined based on 95% confidence concordance or discordance in outcome is tabulated for each matched
intervals, which approximately correspond to a P value of 0.05. An odds set exposed to alternate treatments. Results for each set are plotted on a
ratio, relative risk, or hazard ratio is considered statistically significant if graph, and data collection continues until a preset threshold for a signifi-
the 95% confidence interval does not include 1. An advantage of using cant difference among study groups is crossed or no significant difference
confidence intervals to define statistical significance is that they provide is detected at a given power.12
information on whether a finding is statistically significant and on the
possible range of values for the point estimate in the population, with Statistical Inference
95% certainty.
One pitfall in interpreting statistical significance is ignoring the mag- Statistical testing is used to determine the significance of differences
nitude of an effect in favor of its “significance.” A very large, overpowered among study groups, and thus it provides guidance on whether to accept
study can identify as significant a small, perhaps trivial, difference among or reject the null hypothesis. Although providing details of specific statis-
study groups. Some epidemiologists have proposed that, despite statisti- tical tests is outside the scope of this chapter, Table 1.5 gives examples of
cal significance, odds ratios <2 or 3 in an observational study should not statistical tests that can be applied in analyzing different types of exposure
be interpreted because unidentified bias or confounding could account and outcome variables.
for a difference of this magnitude.9 Conversely, the relative risk or odds Using appropriate analytic and statistical methods is important in
ratio associating an exposure and outcome can be large, but if the expo- identifying significant predictors of an outcome (i.e., risk factors) cor-
sure is uncommon in both groups, it cannot explain most cases of ill- rectly. Confounding variables are associated with the disease of inter-
ness. The public health importance of an exposure can be described by est and with other exposure variables and are not part of the causal
the population-attributable fraction, or the proportion of the disease in a pathway between the other exposure(s) and the outcome. For example,
population that is related to the exposure of interest. consider a study attempting to determine whether meningococcal vac-
cination decreases nasopharyngeal carriage of Neisseria meningitidis. If
Sample Size frequent attendance at social events is associated with increased car-
riage and also with a decreased chance of receiving vaccine, then failure
Another type of error in epidemiologic studies is when a study fails to to adjust for social event attendance as a confounding variable could
identify a true risk factor as statistically significant (designated a type II lead to overestimation of the relationship between vaccination and car-
error, the probability of which is the beta level). The probability of a type riage reduction. Meanwhile, effect modifiers interact with other risk fac-
II error is higher when the sample size is small. Often, the type II error tors to affect their impact on outcome but may or may not be associated
rate is set at 0.2, indicating acceptance of a 20% likelihood that a true dif- with the outcome on their own. Frequently, age is an effect modifier,
ference exists but would not be identified by the study. Statistical power is with an exposure associated significantly with an outcome in one age
defined as 1 − β and is the complement of the probability of committing a group but not in another.
type II error (β); that is, power is the probability of correctly identifying a Several approaches are used to control for confounding variables and
difference of specified size among groups, if such a difference truly exists. effect modifiers. In study design, an extraneous variable can be controlled
The problem of inadequate sample size in clinical studies was highlighted
in an analysis of “negative” randomized controlled trials reported in 3
leading medical journals between 1975 and 1990. Of 70 reports, only 16%
and 36% had sufficient statistical power (80%) to detect a true 25% or TABLE 1.5   Types of Statistical Tests Used to Evaluate the Significance
50% relative difference, respectively, among treatment groups.10 of Associations Among Categorical and Continuous Variables
In calculating sample sizes for testing hypotheses, investigators must
select acceptable rates of type I and type II errors and define the magni- Dependent Variable (Disease, Outcome)
Independent
tude of the difference in outcomes that is deemed clinically important. ­Variable (Exposure, Categorical and
Sample size calculations can be performed using a range of computer soft- Risk ­Factor) Dichotomous Continuous
ware. The program Epi-Info can be used to perform sample size calcula- CATEGORICAL
tions as well as other statistical functions and is available at no charge from
the Centers for Disease Control and Prevention (www.cdc.gov/epiinfo/). Dichotomous Chi-square test Student t-test (parametric)
Ensuring an adequate sample size is particularly important for stud- Fisher exact test Wilcoxon rank sum test
ies attempting to prove equivalence or noninferiority of a new treatment (nonparametric)
compared with standard therapy. Food and Drug Administration guid-
>2 categories Chi-square test Analysis of variance
ance recommends that noninferiority trials adopt a null hypothesis that a ­(parametric)
difference exists among treatments; this hypothesis is rejected if the lower
95% confidence limit for the new treatment is within a specified margin Kruskal-Wallis test
of the point estimate for standard therapy. Because the null hypotheses ­(nonparametric)
can never be proven or accepted, the failure to reject a null hypothesis of CONTINUOUS Logistic regression Linear regression
no difference among treatments or exposure does not prove equivalence.
Correlation (Pearson:
The importance of this distinction is illustrated by an analysis of 25 stud- parametric; Spearman:
ies claiming equivalence of therapies for pediatric bacterial meningitis. nonparametric)
Twenty-three studies claimed equivalence based on a failure to detect a

6
 Principles of Epidemiology and Public Health 1
for by randomization, restricting sampling to one category of the variable confidence limit that is >0% indicates statistically significant protection.
or by frequency matching to obtain similar proportions of cases and con- However, the expected lower confidence limit often is much >0 to be con-
trols in each stratum of the variable. A more extreme form of matching is sistent with meaningful levels of protection. The most important com-
to select control subjects who are similar to individual cases for extrane- ponent of a case-control effectiveness study is selecting control subjects
ous variables (e.g., age, sex, underlying disease) and to analyze whether who have the same opportunity for immunization as do cases. If cases
exposures are concordant or discordant within matched sets. A newer have less opportunity to be immunized, results will be biased toward
approach to study design is the case-crossover14 or case series15 analysis. showing protection. Factors such as low socioeconomic status, which can
In this method, exposures occurring in a defined risk period before the increase the risk of disease and decrease the chance of being immunized,
outcome are compared with exposures occurring outside the risk window are potential confounding variables and can be controlled for by match-
for the same individual subjects. This approach has been adapted to the ing control subjects to cases for those factors.
study of adverse events after vaccination. If the vaccine causes the event, Cohort studies also can be used to determine vaccine effectiveness after
the rate of the event will be greater within a defined risk window than pre- licensure. A study design called the indirect-cohort method was devel-
dicted by chance alone based on the expected distribution of the event.16 oped by researchers at the Centers for Disease Control and Prevention
The strength of this approach is that each subject, or case, serves as his or to evaluate the effectiveness of the pneumococcal polysaccharide vaccine
her own control, thereby decreasing confounding. by using data collected by disease surveillance.18 In this study, the cohort
At the analysis stage, the impact of confounding variables and effect included persons identified with invasive pneumococcal infections. The
modifiers can be limited by performing a stratified analysis or using a study hypothesis was that if pneumococcal vaccines were protective, the
multivariable model. In a stratified analysis, the possible association proportion of vaccinated persons infected with pneumococcal serotypes
between a risk factor and an outcome is determined separately within that are included in the vaccine formulation would be less than the pro-
different categories, or strata, of the extraneous variable. If the extraneous portion of unvaccinated persons infected with vaccine-type strains. Vac-
variable is a confounder, the stratum-specific estimates should be similar cine effectiveness was calculated from the relative serotype distributions
to each other and can be combined into a single estimate using an appro- overall and for each individual serotype. The point estimate of vaccine
priate statistical test (e.g., a Mantel-Haenszel odds ratio). If a stratifica- effectiveness for preventing invasive infection was 57% (95% confidence
tion variable is an effect modifier, the relative risk or odds ratio will differ interval, 45%–66%)19; this estimate is similar to that obtained in a case-
substantially among the strata; for example, an exposure can be a strong control effectiveness study.20
risk factor in one age group but not another. In this setting, a summary
statistic should not be presented, and results for each stratum should be DISEASE CONTROL AND PUBLIC HEALTH POLICY
presented separately. When the extraneous variable is confounding, strat-
ifying the analysis by the confounding variable may eliminate an appar- Outbreak Investigations
ent association between the exposure and the outcome in the unstratified
analysis and indicate that the exposure is not an independent risk factor Outbreak investigations require knowledge of disease transmission and
for disease. use of descriptive and analytic epidemiologic tools. Possible outbreaks
Because stratified analyses become confusing rapidly as the number of can be identified from surveillance data showing an increased rate of an
strata increases, techniques of statistical modeling have been developed infection or an unusual clustering of infection by person, place, or time.
that permit simultaneous control of multiple variables. Significant risk Comparing the incidence rate of disease with a baseline rate from a previ-
factors determined in a multivariable model are interpreted as each con- ous period is helpful in validating the occurrence of an outbreak. Other
tributing independently and significantly to the outcome, as the model explanations for changes in the apparent rate of disease occurrence, such
controls for potential confounding from each included variable. Effect as diagnostic error, seasonal variations, and changes in reporting, must
modification can be taken into account by including terms expressing the be considered.
interaction between a risk factor and effect modifier in the model. Vari- After identifying a potential outbreak, the next steps of an investiga-
ous multivariable models are appropriate for discrete, continuous, and tion are to develop a case definition, identify cases, and characterize the
time-dependent outcomes. descriptive epidemiology of the outbreak. An epidemic curve depicts
A limitation of multivariable modeling is multicollinearity, which the number of cases over time and can provide information on possible
occurs when 2 or more explanatory variables of interest are highly corre- transmission (Fig. 1.1). In an outbreak with a point source exposure, an
lated and can result in inaccurate measures of association and decreased index case may be identified, with other cases occurring after an incuba-
statistical power. The risk of multicollinearity can be reduced by assessing tion period or at multiples of an incubation period. Plotting the location
correlations among potential risk factors and selecting which variables to of cases on a spot map can also be helpful in determining possible expo-
include in the model. Various methods to identify and minimize multi- sures. Describing patients’ characteristics can be important in identify-
collinearity have been developed.17 ing at-risk populations for further investigation or targeting of control
measures, as well as for developing hypotheses that can be investigated
VACCINE EFFICACY AND EFFECTIVENESS STUDIES in an analytic study.
Not all outbreaks can be traced to a point source exposure. Outbreaks
Most prelicensure efficacy studies are experimental, randomized, dou- and epidemics also can result from increased transmission of an endemic
ble-blind, controlled trials in which vaccine efficacy (VE) is calculated disease (i.e., a disease or condition that normally occurs in a specific
by comparing the attack rates (AR) for disease in the vaccinated and population or area). In this situation, it can be challenging to determine
unvaccinated groups: VE (%) = (AR unvaccinated − AR vaccinated) / AR when an increase in disease constitutes an outbreak rather than a nor-
unvaccinated) × 100; or (1 − RR) × 100. mal fluctuation in disease incidence. To determine whether an outbreak
After licensure, conducting controlled studies, which requires with- is occurring, the current incidence of the disease must be compared with
holding vaccine from a control group, is no longer ethical. Therefore, the baseline disease incidence in that area. Often, no standard definition
further studies must be observational rather than experimental, by exists for when an increase in endemic disease incidence constitutes an
comparing persons who have chosen to be immunized with those who outbreak or epidemic. For instance, in US pertussis epidemics the thresh-
have not. Such observational studies are said to assess vaccine effective- old for declaring an epidemic has varied by state. In California in 2010
ness rather than vaccine efficacy; however, the two measures use the same and 2014, an epidemic was declared when the statewide case counts had
abbreviation, VE. In case-control vaccine effectiveness studies, vaccina- reached 5 times the number of cases observed in a year with baseline per-
tion status of persons with disease is compared with vaccination status tussis incidence. By contrast, in Washington State in 2012, an epidemic
of healthy control subjects in a real-world setting. The number of vac- was declared when the incidence of pertussis reached 2 standard devia-
cinated and unvaccinated cases and controls is included in a 2×2 table, tions above the statewide 10-year average.
and vaccine effectiveness is calculated as 1 minus the odds ratio: VE (%) Cohort studies are optimal for investigating outbreaks that occur in
= (1 − OR) × 100. When the proportion of cases vaccinated is less than small, well-defined populations, including in schools, childcare settings,
the proportion of vaccinated controls, the odds ratio is <1, and the point social gatherings, and hospitals. In populations that are large and/or
estimate for VE indicates that immunization is protective. The precision not well defined, a case-control study is the most feasible approach. It is
of the estimate is expressed by the 95% confidence interval. A lower 95% important to select control subjects who had an opportunity equal to that

7
Another random document with
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 “He’s my brother,” I said.
“I don’t care. He wanted to drown me; he didn’t know I can’t die by
water.”
“Can’t you?” I said.
“Of course not. I’m a changeling!”
She said it with a childish seriousness that confounded me.
“What made you one?” I asked.
“The fairies,” she said, “and that’s why I’m here.”
I was too bewildered to pursue the subject further.
“How did you fall in there?” I asked.
“I saw some little fish, like klinkents of rainbow, and wanted to
catch them; then I slipped and soused.”
“Well,” I said, “where are you going now?”
“With you,” she answered.
I offered no resistance. I gave no thought to results, or to what my
father would say when this grotesque young figure should break into
his presence. Mechanically I started for home and she walked by my
side, chatting. Jason strode in our rear, whistling.
“What a brute he must be!” she said once, jerking her head
backward.
“Leave him alone,” I said, “or we shall quarrel. What’s a girl like
you to him?”
I think she hardly heard me, for the whistle had dropped to a very
mellow note. To my surprise I noticed that she was crying.
“I thought changelings couldn’t cry?” I said.
“I tell you water does not affect me,” she answered, sharply. “What
a mean spy you are—for a boy.”
I was very angry at that and strode on with black looks, whereupon
she edged up to me and said, softly: “Don’t be sore with me, don’t.”
I shrugged my shoulders.
“Let’s kiss and be friends,” she whispered.
For the first time in my life I blushed furiously.
“You beast,” I said, “to think that men would kiss!”
She gave me a sounding smack on the shoulder and I turned on
her furiously.
“Oh, yes!” she cried, “hit out at me, do! It’s like you.”
 “I won’t touch you!” I said. “But I won’t have anything more to do
with you,” and I strode on, fuming. She followed after me and
presently I heard her crying again. At this my anger evaporated and I
turned round once more.
“Come on,” I said, “if you want to, and keep a civil tongue in your
head.”
Presently we were walking together again.
“What’s your home, Renny?” she asked, by and by.
“A mill,” I answered, “but nothing is ground there now.”
She stopped and so did I, and she looked at me curiously, with her
red lips parted, so that her teeth twinkled.
“What’s the matter?” said I.
“Nothing,” she said, “only I remember an old, old saying that the
woman told me.”
“What woman?” I asked, in wonder, but she took no notice of my
question, only repeated some queer doggerel that ran somewhat as
follows:
“Where the mill race is
Come and go faces.
Once deeds of violence;
Now dust and silence.
Thither thy destiny
Answer what speaks to thee.”
 CHAPTER III.
THE MILL AND THE CHANGELING.

The outer appearance of the old mill in which we lived and grew
up I have touched upon; and now I take up my pen to paint in black
and white the old, moldering interior of the shell.
The building stood upon a triple arch of red brick that spanned the
stream, and extended from shore to shore, where, on each side, a
house of later date stood cheek to jowl with it. It looked but an
indifferent affair as viewed from the little bridge aforesaid, which was
dedicated to St. Swithun of watery memory, but in reality extended
further backward than one might have suspected. Moreover, to the
east side a longish wing, with a ridged roof of tiles, ran off at right
angles and added considerably to the general dimensions. To the
west stood a covered yard, where once the mill wagons were packed
or unloaded; but this, in all my memory of it, yawned only a dusty
spave, given over to the echoes and a couple of ancient cart wheels
whose rusty tires and worm-pierced hubs were mute evidence of an
inglorious decay.
These were for all to see—but behind the walls!
Was the old mill uncanny from the first, or is it only the ghosts with
which our generation of passions has peopled it that have made it
so? This I can say: That I never remember a time when Jason or I,
or even Zyp, dared to be in the room of silence alone—and in
company never for more than a few minutes. Modred had not the
same awe of it, but Modred’s imagination was a swaddled infant. For
my father I will not speak. Maybe he was too accustomed to specters
to dread them.
This room was one on the floor above the water, and the fact that
it harbored the mill wheel, whose booming, when in motion, shook
the stagnant air with discordant sounds, may have served as some
explanation of its eeriness. It stood against the east wing and away
from the yard, and was a dismal, dull place, like a loft, with black
beams above going off into darkness. Its only light came from a
square little window in front that was bleared with dust and stopped
outside with a lacework of wire. Against its western wall was reared
a huge box or cage of wood, which was made to contain the upper
half of the wheel, with its ratchet and shaft that went up to the great
stones on the floor above; for the mill race thundered below, and
when the great paddles were revolving the water slapped and rent at
the woodwork.
Now it behooves me to mention a strange fancy of my father’s—
which was this, that though no grain or husk in our day ever
crumbled between the stones, the wheel was forever kept in motion,
as if our fortunes lay in grinding against impalpable time. The custom
was in itself ghostly, and its regularity was interrupted only at odd
moments, and those generally in the night, when, lying abed
upstairs, we boys would become conscious of a temporary cessation
of the humming, vibrating noise that was so habitual to the place. To
this fancy was added a strange solicitude on the part of my father for
the well-being of the wheel itself. He would disappear into the room
of silence twice or thrice a day to oil and examine it, and if rarely any
tinkering was called for we knew it by the sound of the closing of the
sluice and of the water rush swerving round by another channel.
Now, for the time I have said enough, and with a sigh return to that
May afternoon and little Zyp, the changeling.
She followed me into the mill so quietly that I hardly heard her step
behind me. When I looked back her eyes were full of a strange
speculation and her hands crossed on her breast, as if she prayed.
She motioned me forward and I obeyed, marveling at my own
submission. I had no slightest idea what I was to say to my father or
what propose. We found him seated by the table in the living room
upstairs, a bottle and glass before him. The weekly demon was
beginning to work, but had not yet obtained the mastery. He stared
at us as we entered, but said nothing.
Then, to my wonder, Zyp walked straight up to the old man, pulled
his arms down, sat upon his knee and kissed his rutted cheek. I gave
a gasp that was echoed by Jason, who had followed and was
leaning against the lintel of the open door. Still my father said nothing
and I trembled at the ominous silence. At last in desperation I
stammered, and all the time Zyp was caressing the passive face.
 “Dad, the girl fell into the water and I pulled her out, and here she
is.”
Then at length my father said in a harsh, deep voice:
“You pulled her out? What was Jason there doing?”
“Waiting for her to drown,” my brother answered for himself,
defiantly forestalling conviction.
My father put the girl from him, strode furiously across the room,
seized Jason by one arm and gave him several cruel, heavy blows
across his shoulders and the back of his head. The boy was half
stunned, but uttered no cry, and at every stroke Zyp laughed and
clapped her hands. Then, flinging his victim to the floor, from which
he immediately rose again and resumed his former posture by the
door, pale but unsubdued, my father returned to his seat and held
the girl at arm’s length before him.
“Who are you?” he said.
She answered, “A changeling,” in a voice soft as flowers.
“What’s your name?”
“Zyp.”
“Your other name?”
“Never mind; Zyp’s enough.”
“Is it? Where do you come from? What brings you here?”
“Renny brought me here because I love him.”
“Love him? Have you ever met before?”
“No; but he pulled me out of the water.”
“Come—this won’t do. I must know more about you.”
She laughed and put out her hand coaxingly.
“Shall I tell you? A little, perhaps. I am from a big forest out west
there, where wheels drone like hornets among the trees and black
men rise out of the ground. I have no father or mother, for I come of
the fairies. Those who stood for them married late and had a baby
and they delayed to christen it. One day the baby was gone and I
was there. They knew me for a changeling from the first and didn’t
love me. But I lived with them for all that and they got to hate me
more and more. Not a cow died or a gammer was wryed wi’ the
rheumatics but I had done it. Bit by bit the old man lost all his trade
and loved me none the more, I can tell you. He was a Beast Leech,
and where was the use of the forest folk sending for him to mend
their sick kine when he kept a changeling to undo it all? At last they
could stand no more of it and the woman brought me away and lost
me.”
“Lost you?” echoed my father.
“Oh,” said Zyp, with a little cluck, “I knew all along how the tramp
was to end. There was an old one, a woman, lived in the forest, and
she told me a deal of things. She knew me better than them all, and I
loved her because she was evil, so they said. She told me some
rhymes and plenty of other things.”
“Well?” said my father.
“We walked east by the sun for days and days. Then we came to
the top of a big, soft hill, where little beetles were hopping among the
grass, and below us was a great town like stones in a green old
quarry, and the woman said: ‘Run down and ask the name of it while
I rest here.’ And I ran with the wind in my face and was joyful, for I
knew that she would escape when I was gone, and I should never
see her again.”
“And then you tumbled into the water?” said my father.
Zyp nodded.
“And now,” she said, “I belong to nobody, and will you have me?”
My father shook his head, and in a moment sobs most piteous
were shaking the girl’s throat. So forlorn and pretty a sight I have
never seen before or since.
“Well,” he said, “if nobody comes to claim you, you may stop.”
And stop Zyp did. Surely was never an odder coming, yet from
that day she was one of us.
What was truthful and what imaginative in her story I have never
known, for from first to last this was the most we heard of it.
One thing was certain. Zyp was by nature a child of the open air
and the sun. Flowers that were wild she loved—not those that were
cultivated, however beautiful, of which she was indifferent—and she
had an unspeakable imagination in reading their fanciful histories
and a strange faculty for fondling them, as it were, into sentient
beings. I can hardly claim belief when I say that I have seen a rough
nettle fade when she scolded it for stinging her finger, or a little
yellow rock rose turn from the sun to her when she talked to it.
 Zyp never plucked a flower, or allowed us to do so if she could
prevent it. I well remember the first walk I took with her after her
establishment in the mill, when I was attracted by a rare little
blossom, the water chickweed, which sprouted from a grassy trench,
and pulled it for her behoof. She beat me savagely with her soft
hands, then fell to kissing and weeping over the torn little weed,
which actually appeared to revive a moment under her caresses. I
had to promise with humility never to gather another wild flower so
long as I lived, and I have been faithful to my trust.
The afternoon of her coming old Peg rigged her up some
description of sleeping accommodation in a little room in the attic,
and this became her sanctuary whenever she wished to escape us
and be alone. To my father she was uniformly sweet and coaxing,
and he for his part took a strange fancy to her, and abated somewhat
of his demoniacal moodiness from the date of her arrival.
Yet it must not be imagined, from this description of her softer side,
that Zyp was all tender pliability. On the contrary, in her general
relations with us and others as impure human beings, she was the
veritable soul of impishness, and played a thousand pranks to prove
her title to her parentage.
At first she made a feint of distributing her smiles willfully, by turn,
between Modred and me, so that neither of us might claim
precedence. But Jason was admitted to no pretense of rivalry;
though, to do him justice, he at once took the upper hand by meeting
scorn with indifference. In my heart, however, I claimed her as my
especial property; a demand justified, I felt no doubt, by her manner
toward me, which was marked by a peculiar rebellious tenderness
she showed to no other.
The day after her arrival she asked me to take her over the mill
and show her everything. I complied when the place was empty of all
save us. We explored room by room, with a single exception, the
ancient building.
Of course Zyp said: “There’s a room you haven’t shown me,
Renny.”
“Yes,” said I; “the room of silence.”
“Why didn’t we go there?”
“Never mind. There’s something wicked in it.”
 “What? Do tell me! Oh, I should love to see!”
“There’s nothing to see. Let it alone, can’t you?”
“You’re a coward. I’ll get the sleepy boy to show me.”
“Come along then,” I said, and, seizing her hand, dragged her
roughly indoors.
We crossed a dark passage, and, pushing back a heavy door of
ancient timber, stood on the threshold of the room of silence. It was
not in nature’s meaning that the name was bestowed, for, entering,
the full voice of the wheel broke upon one with a grinding fury that
shook the moldering boards of the floor.
“Well,” I whispered, “have you seen enough?”
“I see nothing,” she cried, with a shrill, defiant laugh; “I am going
in”—and before I could stop her, she had run into the middle of the
room and was standing still in the bar of sunlight, with her arms
outspread like wings, and her face, the lips apart, lifted with an
expression on it of eager inquiry.
What happened? I can find an image only in the poison bottle of
the entomologist. As some shining, flower-stained butterfly, slipped
into this glass coffin, quivers, droops its wings and fades, as it were,
in a moment before its capturer’s eyes, so Zyp faded before mine.
Her arms dropped to her sides, her figure seemed as if its whole
buoyancy were gone at a touch, her face fell to a waxen color and
“Oh, take me away!” she wailed in a thin, strangled voice.
I conquered my terror, rushed to her, and, dragging her stumbling
and tripping from the room, banged to the door behind us and made
for the little platform once more and the open air.
She revived in a wonderfully short space of time, and, lifting up her
head, looked into my eyes with her own wide with dismay.
“It was hideous,” she whispered; “why didn’t you stop me?”
Zyp, it will be seen, was not all elf. She had something in common
with her sex.
“I warned you,” I said, “and I know what you felt.”
“It was as if a question was being asked of me,” she said, in a low
voice. “And yet no one spoke and there was no question. I don’t
know what it wanted or what were the words, for there were none;
but I feel as if I shall have to go on thinking of the answer and
struggling to find it forever and ever.”
 “Yes,” I whispered, in the same tone; “that is what everybody
says.”
She begged me not to follow her, and crept away quite humbled
and subdued, and we none of us saw more of her that day. But just
as she left me she turned and whispered in awe-stricken tone,
“Answer what speaks to thee,” and I could not remember when and
where I had heard these words before.
 CHAPTER IV.
ZYP BEWITCHES.

In the evening Dr. Crackenthorpe paid us a visit. He found my

father out, but elected to sit with us and smoke his pipe expectant of
the other’s return.
He always treated us boys as if we were so much dirt, and we
respected his strength just sufficiently to try no pranks on him in the
absence of the ruling power. But nevertheless we resented his
presumption of authority, and whenever he sat with us alone made
an exaggerated affectation of being thick in whispered confidences
among ourselves.
Zyp was still upstairs and the doctor had not as yet seen her, but
he was conscious, I think, in some telepathic way, of an alien
presence in the house, for he kept shifting his position uneasily and
looking toward the door. A screech from his lips suddenly startled us,
and we turned round to see the long man standing bolt upright, with
his face gone the color of a meal sack, and his bold eyes staring
prominent.
“What’s the matter?” said Jason.
Gradually the doctor’s face assumed a dark look of rage.
“Which of you was it?” he cried in a broken voice; “tell me, or I’ll
crack all your fingers up like fire sticks!”
“What’s the matter?” said Jason, again; “you see for yourself
we’ve been sitting by the table all the time you’ve been there.”
“Something spoke—somebody, I tell you, as I sat here in the
chimney corner!” He was beside himself with fury and had great ado
to crush his emotion under. But he succeeded, and sat down again
trembling all over.
“A curse is on the house!” he muttered; then aloud: “I’ve had
enough of your games, you black vermin! I won’t stand it, d’ye hear?
Let there be an end!”
We stared, dropped into our seats and were beginning our
confidences once more, when the doctor started up a second time
with a loud oath, and leaped into the middle of the room.
“Great thunder!” he shouted; “d’ye dare!”
This time we had all heard it—a wailing whisper that seemed to
come from the neighborhood of the chimney and to utter the words:
“Beware the demon that sits in the bottle,” and of the whole company
only I was not confounded.
As to the doctor, he suddenly turned very white again, and
muttered shakingly: “Can it be? I don’t exceed as others do. I swear I
have taken less this month than ever before.”
With the terror in his soul he stumbled toward the door and was
moving out his hand to reach it, when it opened from the other side
and Zyp, as meek and pure looking as a young saint, met him on the
threshold.
Now, I had that morning, in the course of conversation with the
changeling, touched upon Dr. Crackenthorpe and his weaknesses,
and that ghostly mention of the bottle convinced me on the moment
that only she could be responsible for the mystery—a revelation of
impishness which, I need not say, delighted me. The method of her
prank I may as well describe here. The embrasure for a fireplace in
her room had never been fitted with a grate, and the hearthstone
itself was cracked and dislocated in a dozen places. By removing
some of these fragments she had actually discovered a broken way
into the chimney of the sitting room below, down which it was easy to
slip a hollow rail of iron which with other lumber lay in the attic. This
she had done, listened for her opportunity, and thereupon spoken
the ominous words.
I think her appearance was the consummation of the doctor’s
terror, for a shuddering “Oh!” shook from his lips, and he seemed
about to drop. And indeed she was somewhat like a spirit, with her
wild white face looking from a tangle of pheasant-brown hair and her
solemn eyes like water glints in little wells of shadow.
She walked past the stricken man all stately, and then Modred and
I jumped up and greeted her. At this the doctor’s jaw dropped, but
his trembling ceased and he watched us with injected eyes. Holding
my two hands, Zyp looked coyly round, leaning backward.
“I love a tall man,” she whispered; “he has more in him than a
short one.”
 The doctor pulled himself together and came straggling across to
the table.
“Who the pestilence is this?” he said, in a voice not yet quite under
his command.
Zyp let go my hands and curtsied like a wild flower.
“Zyp, the orphan, good gentleman,” she said; “shall I fill your pipe
for you?”
It had fallen on the floor by the chimney, and she picked it up and
went to him with a winning expression.
“Where is your tobacco, please?”
Mechanically he brought a round tin box from his pocket and
handed it to her. Then it was a study in elfin coquetry to see the way
in which she daintily coaxed the weed into the bowl and afterward
sucking at the pipe stem with her determined little red lips to see if it
drew properly. This done, she presented the mouthpiece to the
doctor’s consideration, as if it were a baby’s “comforter.”
“Now,” she said, “sit down and I’ll bring you your glass.”
But at this the four of us, including Dr. Crackenthorpe, drew back.
My father was no man to allow his pleasures to be encroached upon
unbidden, and we three, at least, knew it as much as our skins were
worth to offer practical hospitality in his absence.
Zyp looked at our faces and stamped her foot lively, with a toss of
disdain.
“Where is the strong drink?” she said.
Modred tittered. “In that cupboard over the mantel shelf, if you
must know,” he said.
Zyp had the bottle out in a twinkling and a glass with it. She
poured out a stiff rummer, added water from a stone bottle on a
corner shelf, and presented the grateful offering to the visitor, who
had reseated himself by the table.
His scruples of conscience and discretion grew faint in the near
neighborhood of the happy cordial. He seized the glass and
impulsively took half the grog at a breath. Zyp clapped her hands
joyfully, whereupon he clumped down the glass on the table with a
dismayed look.
“Well,” he said, “you’re an odd little witch, upon my word. What
Robin Goodfellow fathered you, I should like to know?”
 “He’s no father,” said Zyp. “He’s too full of tricks for a family man. I
could tell you things of him.”
“Tell us some then,” said the doctor.
What Zyp would have answered I don’t know, for at that moment
my father walked into the room. If he had had what is vulgarly called
a skinful, he was not drunk, for he moved steadily up to the little
group at the table with a scowl contracting his forehead. The half-
emptied tumbler had caught his eye immediately and he pointed to it.
I was conscious that the doctor quaked a little.
“Pray make yourself at home,” said my father, and caught up the
glass and flung its contents in the other’s face. In a moment the two
men were locked in a savage, furious embrace, till, crashing over a
chair, they were flung sprawling on the floor and apart. Before they
could come together again Zyp alone of us had placed herself
between them, fearless and beautiful, and had broken into a quaint
little song:
“Smooth down her fur,
Rub sleep over her eyes,
Sweet, never stir.
Kiss down the coat of her
There, where she lies
On the bluebells.”
She sung, and whether it was the music or the strangeness of the
interruption, I shall never know; only the wonderful fact remains that,
with the sound of her voice, the great passion seemed to die out of
the two foes and to give place to a pleasant conceit, comical in its
way, that they had only been rollicking together.
“Well,” said my father, without closer allusion to his brutality, “the
liquor was choice Schiedam, and it’s gone.”
He sat down, called for another glass, helped himself to a noggin
and pushed the bottle roughly across to Dr. Crackenthorpe, who had
already reseated himself opposite.
“Sing again, girl,” said my father, but Zyp shook her head.
“I never do anything to order,” she said, “but the fairies move me to
dance.”
 She blew out the lamp as she spoke and glided to a patch of light
that fell from the high May moon through the window on to the rough
boards of the room. Into this light she dipped her hands and then
passed them over her hair and face as though she were washing
herself in the mystic fountain of the night; and all the time her
murmuring voice accompanied the action in little trills of laughter and
words not understandable. Presently she fell to dancing, slowly at
first and dividing her presence between glow and gloom; but
gradually the supple motion of her body increased, step by step, until
she was footing it as wildly as a young hamadryad to her own
leaping shadow on the floor.
Suddenly she sprung from the moonlit square, danced over to Dr.
Crackenthorpe and, whispering awfully in his ear, “Beware the
demon that sits in the bottle,” ran from the room.
My father burst into a fit of laughter, but I think from that day the
doctor fully hated her.
 CHAPTER V.
A TERRIBLE INTERVIEW.

Zyp had been with us a month, and surely never did changeling
happen into a more congenial household.
Jason she still held at arm’s length, which, despite my admiration
of my brother, I secretly congratulated my heart on, for—let me get
over it at the outset—from first to last, I have never wavered in my
passion of love for this wild, beautiful creature. The unexpectedness
of her coming alone was a romance, the delight of which has never
palled upon me with the deadening years. Therefore it was that I
early made acquaintance with the demon of jealousy, than whom
none, in truth, is more irresistible in his unclean strength and
hideousness.
Zyp and I were one day wandering under the shadow of the
mighty old cathedral of Winton.
“I don’t like it, Renny,” she said, pressing up close to me. “It’s awful
and it’s grand, but there are always faces at the windows when I look
up at them.”
“Whose?” I said, with a laugh.
“I don’t know,” she said; “but think of the thousands of old monks
and things whose home it was once and whose ghosts are shut up
among the stones. There!” she cried, pointing.
I looked at the old leaded window she indicated, but could see
nothing.
“His face is like stone and he’s beckoning,” she whispered. “Oh,
come along, Renny”—and she dragged me out of the grassy yard
and never stopped hurrying me on till we reached the meadows.
Here her gayety returned to her, and she felt at home among the
flowers at once.
Presently we wandered into a grassy covert against a hedge on
the further side of which a road ran, and threw ourselves among the
“sauce alone” and wild parsley that grew there. Zyp was in one of
her softest moods and my young heart fluttered within me. She
leaned over me as I sat and talked to me in a low voice, with her fair
young brow gone into wrinkles of thoughtfulness.
“Renny, what’s love that they talk about?”
I laughed and no doubt blushed.
“I mean,” she said, “is it blue eyes and golden hair or brown eyes
and brown hair? Don’t be silly, little boy, till you know what I mean.”
“Well, what do you mean, Zyp?”
“I want to know, that’s all. Renny, do you remember my asking to
kiss and be friends that day we first met, and your refusing?”
“Yes, Zyp,” I stammered.
“You may kiss me now, if you like,” and she let herself drop into my
arms, as I sat there, and turned up her pretty cheek to my mouth.
My blood surged in my ears. I was half-frightened, but all with a
delicious guilt upon me. I bent hastily and touched the soft pink curve
with my trembling lips.
She lay quite still a moment, then sat up and gently drew away
from me.
“No,” she said, “that isn’t it. Shall I ever know, I wonder?”
“Know what, Zyp?”
“Never mind, for I shan’t tell you. There, I didn’t mean to be rude,”
and she stroked the sleeve of my jacket caressingly.
By and by she said: “I wonder if you will suffer, Renny, poor boy? I
would save you all if I could, for you’re the best of them, I believe.”
Her very words were so inexplicable to me that I could only sit and
stare at her. I have construed them since, with a knife through my
heart for every letter.
As we were sitting silent a little space, steps sounded down the
road and voices with them. They were of two men, who stopped
suddenly, as they came over against us, hidden behind the hedge,
as if to clinch some argument, but we had already recognized the
contrary tones of my father and Dr. Crackenthorpe.
“Now, harkee!” the doctor was saying; “that’s well and good, but
I’m not to be baffled forever and a day, Mr. Ralph Trender. What
does it all amount to? You’ve got something hidden up your sleeve
and I want to know what it is.”
“Is that all?” My father spoke in a set, deep manner.
“That’s all, and enough.”
 “Then, look up my sleeve, Dr. Crackenthorpe—if you can.”
“I don’t propose to look. I suggest that you just shake it, when no
doubt the you-know-whats will come tumbling out.”
“And if I refuse?”
“There are laws, my friend, laws—iniquitous, if you like; but, for
what they are, they don’t recognize the purse on the highway as the
property of him that picks it up.”
“And how are you going to set these laws in motion?”
“We’ll insert the end of the wedge first—say in some public print,
now. How would this look? We have it on good authority that Mr.
Trender, our esteemed fellow-townsman, is the lucky discoverer of
——”
“Be silent, you!” My father spoke fiercely; then added in a low tone:
“D’ye wish all the world to know?”
“Not by any means,” said the other, quietly, “and they shan’t if you
fall in with my mood.”
“If I only once had your head in the mill wheel,” groaned my father,
with a curse. “Now, harken! I don’t put much value on your threat; but
this I’ll allow that I court no interference with my manner of life. Take
the concession for what it is worth. Come to me by and by and you
shall have another.”
“A couple,” said the doctor.
“Very well—no more, though I rot for it—and take my blessing with
them.”
“When shall I come?” said the doctor, ignoring the very equivocal
benediction.
“Come to-night—no, to-morrow,” said my father, and turning on his
heel strode heavily off toward the town.
I heard the doctor chuckling softly with a malignant triumph in his
note.
I clenched my teeth and fists and would have risen had not Zyp
noiselessly prevented me. It was wormwood to me; the revelation
that, for some secret cause, my father, the strong, irresistible and
independent, was under the thumb of an alien. But the doctor walked
off and I fell silent.
On our homeward way we came across Jason lying on his back
under a tree, but he took no notice of us nor answered my call, and
Zyp stamped her foot when I offered to delay and speak to him.
Nevertheless I noticed that more than once she looked back, as long
as he was in view, to see if he was moved to any curiosity as to our
movements, which he never appeared to be in the least.
Great clouds had been gathering all the afternoon, and now the
first swollen drops of an advancing thunderstorm spattered in the
dust outside the yard. Inside it was as dark as pitch, and I had
almost to grope my way along the familiar passages. Zyp ran away
to her own den.
Suddenly, with a leap of the blood, I saw that some faintly pallid
object stood against the door of the room of silence as I neared it. It
was only with an effort I could proceed, and then the thing detached
itself and was resolved into the white face of my brother Modred.
“Is that you, Renny?” he said, in a loud, tremulous voice.
“Yes,” I answered, very shakily myself. “What in the name of
mystery are you doing there?”
“I feel queer,” he said. “Let’s get to the light somewhere.”
We made our way to the back, opened the door leading on to the
little platform and stood looking at the stringed rain. Modred’s face
was ghastly and his eyes were awakened to an expression that I had
never thought them capable of.
“You’ve been in there?” I said.
“Yes,” he whispered.
“More fool you. If you like to tempt the devil you should have the
brass to outface him. Why, you’ve got it!” I cried, for he suddenly let
fall from his trembling hand a little round glittering object, whose
nature I could not determine in the stormy twilight.
He had it in his clutch again in a moment, though I pounced for it,
and then he backed through the open doorway.
“It’s naught that concerns you,” he said; “keep off, you beast!”
“What is it?” I cried.
“Water-parings,” said he, and clapped to the door in my face as I
rushed at him, and I heard him scuttle upstairs. The latch caught me
in the chest and knocked my breath out for a bit, so that I was unable
to follow, and probably he ran and bolted himself into his bedroom. In
any case, I had no mind for pursuit, my heart being busy with other
affairs; and there I remained and thought them out. Presently, being
well braced to the ordeal, I went indoors and upstairs to the living
room, where I was persuaded I should find my father. And there he
sat, pretty hot with drink and with a comfortless, glowering devil in
his eyes.
“Well!” he thundered, “what do you want?”
I managed to get out, with some firmness, “A word with you, dad,”
though his eyes disquieted me.
“Make it one, then, and a quick one!”
“Zyp and I were sitting behind a hedge this afternoon when you
and Dr. Crackenthorpe were at words on the other side.”
His eyes shriveled me, but the motion of his lips seemed to signify
to me that I was to go on.
“Dad, if he has any hold over you, let me share the bother and
help if I can.”
He had sat with his right hand on the neck of the bottle from which
he had been drinking, and he now flung the latter at me, with a snarl
like that of a mad dog. Fortunately for me, in the very act some flash
of impulse unnerved him, so that the bottle spun up to the ceiling and
crashed down again to the floor, from which the scattered liquor sent
up a pungent, sickening odor. Then he leaped to his feet and yelled
at me. I could make nothing of his words, save that they clashed into
one another in a torrent of furious invective. But in the midst his
voice stopped, with a vibrating snap; he put his hand to his forehead,
which, I saw with horror, was suddenly streaked with purple, and
down he sunk to the floor in a heap.
I was terribly frightened, and, running to him, endeavored in a
frantic manner to pull him into a sitting posture. I had half succeeded,
when, lying propped up against the leg of the table, he gave a groan
and bade me in a weak voice to let him be; and presently to my joy I
saw the natural color come back to his face by slow degrees. By and
by he was able to slide into the chair he had left, where he lay
panting and exhausted, but recovering.
“Renalt, my lad,” he said, in a dragging voice, “what was that you
said just now? Let’s have it again.”
I hesitated, but he smiled at me and bade me not to fear. Thus
encouraged, I repeated my statement.
“Ah,” he said; “and the girl—did she hear?”
 “She couldn’t help it, dad. But she can’t have noticed much, for
she never even referred to it afterward.”
“Which looks bad, and so much for your profound knowledge of
the sex.”
He looked at me keenly for some moments from under his matted
eyebrows; then muttered as if to himself:
“Here’s a growing lad, and loyal, I believe. What if I took him a
yard into my confidence?”
“Oh, yes, dad,” I said, eagerly. “You can trust me, indeed you can.
I only want to be of some use.”
He slightly shook his head, then seemed to wake up all of a
sudden.
“There,” he said; “be off, like a good boy, and don’t worry me a
second time. You meant well, and I’m not offended.”
“Yes, dad,” I said a little sadly, and was turning to go, when he
spoke to me again:
“And if the girl should mention this matter—you know what—to
you, say what I tell you now—that Dr. Crackenthorpe thinks your
father can tell him where more coins are to be found like the one I
gave him that night; but that your father can’t and is under no
obligation to Dr. Crackenthorpe—none whatever.”
So I left him, puzzled, a little depressed, but proud to be the
recipient of even this crumb of confidence on the part of so reserved
and terrible a man.
Still I could not but feel that there was something inconsistent in
his words to me and those I had heard him address to the doctor.
Without a doubt his utterances on the road had pointed to a certain
recognition of the necessity of bribing the other to silence.