Pediatrics.
`v. 128, no. 6 (Dec. 2011)
`General Collection
`W1 PE191
`2012-01—18 09:08:58
`
`AMERICAN ACADEMY OF PEDIATRICS
`
`1 LUEATRICS®
`
`DECEMBER 2011 ' VOLUME 128
`
`NUMBER 6
`
`wwwpediatrioscrg
`
`Antibiotic Prescribing in Ambulatory Pediatrics
`A l. Hersh eta] 1055
`
`Pediatric Antimicrobial Stewardship M. C. Di Pant/ma of n/
`1002
`I
`
`Infant Varicella in the US 8. S. Chaves of n/ 1071
`Adolescent Vaccination-Coverage Levels in the us; 2006 _2|109
`S. Slokley of a/ 1078
`Financial Impact to Providers Using Combination Vaccines
`A, K Shon of o/ 1087
`
`Pediatricians‘ Views on Alternative Immunization
`Schedules A. Wightman er al 1094
`Infant Sleep Following Immunization: An RCT L Franck er a/
`1100
`
`Welfare and Childhood Vaccination MEW. Sohn at a/
`
`1 109
`
`PEDIATRICS PERSPECTIVES
`Limits of Viability in the United States 8. H. Arzuaga er al
`1047
`
`STATE-OF-THE-ART REVlEW ARTICLE
`
`Recent Advances in HAE N. Sardano and I J. Craig 1 175
`
`'sPEcIALARTICLEs
`Acetaminophen and Asthma J.
`
`l. McBr/de l 181
`
`Contemporary Ethical Issues in Human Milk Banking
`D. J. Miracle at al 1186
`
`COMMENTARY
`
`Reflections on U.S. Immunization Challenges F. K. Morouse
`1 192
`
`Abstracts appear on pages 1195—1210
`
`11:14 mg;
`
`
`l. Roppuporr (:1 (1/ 1207
`Medication Recgnciliation D,
`Improving Reporting of Outpatient Medical Errors
`0. R. Neusplelot a/ 1207
`
`Exclusive Breastfeeding in the US J. R, Jones et al
`Paternal and Child Mental Health Problems
`M. Weitzman of 0/
`l 126
`
`l 117
`
`Antipsychotic Medication Use in Children
`8. E. Andrade et a/ 1155
`
`Effects of a Night-Team System on Sleep and Work Hours
`K.—P. Chua at a/
`1 142
`
`Weight and Crash-Related Injury M. R. Zonfri/Io et al 1148
`Delayed Acyclovir and Mortality in Neonatal HSV
`5‘. 8. Shah of a/ 1155
`Outcomes of Children With Eczema Herpeticum
`P. L. Aronson et al 1161
`
`Role of Reputation in Pediatric Specialties Ranking
`RA. Bush et al 1168
`
`CASE REPORTS—wwwpedlatr‘icsorg
`Stress Hyperglycemia in Children and Familial Diabetes
`T. Oran et a/ 1208
`
`Paracetamol and PDA Constriction G. Hommerman er a! 1208
`Myocardial Infarction, Synthetic Cannabis K2 A. Mr at a/
`1208
`
`Intravenous lipid Emulsion for TCA Overdose in a Toddler
`0. Hendron er al 1208
`Treatment of Kimura Disease With IVIG
`V. Hernandez—Bautisra er a/ 1209
`Clinical and Biochemical Characterization of cblF Disease
`0. Glad/pa et al 1209
`
`FROM THE AMERICAN ACADEMY OF PEDIATRICS
`Meningococcal Conjugate Vaccine Booster Dose
`Recommendations Committee on Infect/cue Diseases 1215
`Health Care for Youth in the Juvenile Justice System
`P. K Bravermon 1219
`Positional Skull Deformities in Infants J. Laugh/in,
`I G. Luerssen, M. S. 0/03, the Committee on Praorloe and
`Ambulatory Med/Cine, and Section on Neurological Surgery
`1256
`
`
`
`Panel on Integrated Guidelines for Cardiovascular
`Health and Risk Reduction in Children and Adolescents:
`Summary Report R E. W Kovey, D. G. Simons—Morton,
`and J. M. de Jesus, Supplement Editors S215
`
`American Academy of Pediatrics
`DEDICATED TO THE HEALTH OF ALI. CHILDREN“
`
`
`
`Page 1 of 17
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`CSL EXHIBIT 1020
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`CSL V. Shire
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`CSL EXHIBIT 1020
`CSL v. Shire
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`Page 1 of 17
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`

`

`The content of the journal is
`
`intended to encompass the
`
`needs of the whole child in his
`
`physiologic, mental, emotional,
`and social structure,
`
`The single word, PEDIATRICS,
`has been chosen to indicate this
`
`catholic intent.
`
`Hugh McCulloch
`PEDIATRICS, January I948
`
`Editor
`Lewis R. First, Burlington, VT
`
`Deputy Editor
`Virginia A, Moyer, Houston, TX
`Editor Emeritus
`Jerold F. Lucey, Burlington, VT
`Associate Editors
`Phyllis A. Dennery, Philadelphia, PA
`Jeffrey D. Horbar, Burlington, VT
`J. Jeffrey Malatack, Wilmington, DE
`William V. Raszka, Burlington, VT
`Gordon Schutze, Houston, TX
`
`Assistant Editors
`Alex Kemper, Durham, NC
`Claudia Kozinetz, Houston, TX
`Diane Duvall Marshall, Chapel Hill, NC
`Rachel Y. Moon, Bethesda, MD
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`Senior Managing Editor
`Joe Puskarz, Elk Grove Village, IL
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`Managing Editor
`Alain Douglas Park, Elk Grove Village, IL
`Editorial Associates
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`Gia Gustilo, Houston, TX
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`Kathryn Sparks, Elk Grove Village, lL
`Deanna Stoppler, Burlington, VT
`
`Editorial Board
`iichatd Bachur, Boston, MA
`Susan Baker, Buffalo, NY
`A. Wesley Burks, Durham, NC
`,atha Chandran, Nesconset, NY
`Vincent Chiang, Boston, lle
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`Barbara Cromer, Cleveland, OH
`Eric Eichenwald, Houston, TX
`Gary Freed, Ann Arbor, MI
`_ydia Furman, Cleveland, OH
`Stephen J. Harris, San Jose, CA
`Helen Lauro, Brooklyn, NY
`Alex Levin, Philadelphia, PA
`Donald E. Lighter, Knoxville, TN
`Reuben Matalon, Galveston, TX
`ebecka Meyers, Salttake City, UT
`Thomas Newman, San Francisco, CA
`iichard L. Saphir, New York, NY
`Joann Schulte, Atlanta, GA
`Gary Smith, Columbus, OH
`Tina Tan, Chicago, IL
`iobert Voigt, Houston, TX
`Steven Zeichner, Bethesda, MD
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`Ex Officio
`0. Marion Burton, President
`Errol R. Alden, Executive Director
`
`
`
`Journal Production Manager
`Denise Stanley, Columbia, MD
`
`
`Publisher
`American Academy of Pediatrics
`Robert Perelman, Director, Department of Education
`Michael Held, Director, Division ofScho/ar/y Journals
`and Professional Periodicals
`
`PEDIATRICS (ISSN 0031 4005) is owned and controlled by the American Academy of Pediatrics. it is published monthly
`by the American Academy of Pediatrics, Elk Grove Village, IL 600074 098.
`Copyright ID 201 I by the American Academy of Pediatrics. All Rights Reserved. Printed in USA. Authorization to
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`

`

`PEDIATRICS”
`
`DECEMBER 201i
`
`' VOLUME I28 ' NUMBER 6
`
`Most of the articles in PEDIATRICS have more
`content available online at www.pediatrics,org.
`
`= data file available online
`
`,x
`
`= podcast available online
`g = video available online
`@ = free access online
`
`= funded by NIH
`
`
`
`General Information
`
`PEDIATRICS PERSPECTIVES
`
`Limits of Human Viability in the United States: A
`Medicolegal Review Bonnie Hope Arzuaga, Ben Hokew Lee
`
`ARTICLES
`
`Antibiotic Prescribing in Ambulatory Pediatrics in the
`United States Adam L Hersh, Daniel J Shapiro,
`Andrew T. Pavia, Samir Si Shah
`
`Benefits of a Pediatric Antimicrobial Stewardship
`Program at a Children’s Hospital Mi Cecilia Di Pentima,
`Shannon Chan, Jobayer Hossain
`
`Varicella in Infants After Implementation of the US
`Varicella Vaccination Program Sandra 8. Chaves,
`Adriana S, Lopez, Tare/(a Li Watson, Rachel Given,
`Barbara Watson, Laurene Mason/a, Jane F. Seward
`
`Adolescent Vaccination-Coverage Levels in the United
`States: 2006 -2009 Shannon Stokley, Amanda Colin,
`Christina Dore/l, Susan Hariri, David Yankey,
`Nancy Messonn/er, Pascale M. Wortley
`
`Financial Impact to Providers Using Pediatric
`Combination Vaccines Angela K. Sheri, Elizabeth Sobczyk,
`Lone Simonsen, Farid Khan, Allahna Esber,
`Margie a Andreae
`
`Washington State Pediatricians’ Attitudes Toward
`Alternative Childhood Immunization Schedules
`Aaron Wightman, Douglas J. Opel, Edgar K Marcuse,
`James A. Taylor
`
`Infant Sleep After Immunization: Randomized Controlled
`Trial of Prophylactic Acetaminophen Linda Franck,
`Caryl L. Gay, Mary Lynch, Kathryn A Lee
`
`Page 3
`
`Thi5 material was copied
`atthE NLM and maybe
`Su b'ect US CD riiht Laws
`
`American Academy of Pediatrics (S
`DEDICATED 'I'() THE HEAL’I'H OF ALI. CHILDREN"
`
`Page 3 of 17
`
`

`

`PEDIATRICS”
`
`DECEMBER 20H - VOLUME 128 ' NUMBER 6
`
`Welfare, Maternal Work, and Dn-Time Childhood
`Vaccination Rates Min—Woong Sohn, Joan Yoo, Elissa H. on,
`Laura B. Amsden, Jane l. Ho/l
`
`Factors Associated With Exclusive Breastfeeding in the
`United States Jessica R. Jones, Michael D. Kogan,
`Gopa/ K. Singh, Deborah L Dee, Laurence M. Crummer—Strawn
`
`Paternal Depressive Symptoms and Child Behavioral
`or Emotional Problems in the United States
`Michael Weitzman, David C, Rosenthal, Ying-Hua tiu
`
`Antipsychotic Medication Use Among Children and
`Risk of Diabetes Mellitus Susan E. Andrade, Joan C. Lo,
`Douglas Rob/in, Hassan Fouayzi, Daniel F. Connor,
`Robert B. Penfo/d, Malini Chandra, George Reed,
`Jerry H. Curwitz
`
`Effects of a Night-Team System on Resident Sleep and
`Work Hours Koo-Ping Chua, Mary Beth Cordon,
`Theodore Sectish, Christopher P. tandrigan
`
`Association Between Weight and Risk of Crash-Related
`Injuries for Children in Child Restraints Mark R. Zonfri/lo,
`Michael R. Elliott, Carol A. Flannagan, Dennis R. Durbin
`
`Delayed Acyclovir Therapy and Death Among Neonates
`With Herpes Simplex Virus Infection Sam/r S. Shah,
`Pauli. Aronson, Zoinab Mohamad, Scott/I. torch
`
`Delayed Acyclovir and Outcomes of Children
`Hospitalized With Eczema Herpeticum Paul L Aronson,
`Albert C. Yon, Mano] K. Mittal, Zeinab Mohamed Sam/r S. Shah
`
`Role of Reputation in Top Pediatric Specialties Rankings
`Ruth A. Bush, EdwardJ Ouig/ey, tyman Fox, Ivan Garcia-Bassets
`
`REVIEW ARTICLES
`
`e~review articles—wwwpediatricsorg
`Management of Children With Sickle Cell Disease:
`A Comprehensive Review of the Literature
`Patricia l. Kavanagh, Philippa C. Sprinz, Samuel R. Vinci,
`Howard Bauchner, 0. Jason Wang
`
`@
`
`The Safety of Pediatric Acupuncture: A Systematic
`Review Denise Adams, Florence Cheng, Hsing Jou,
`Steven Aung, Yutaka Yasui, Sun/ta Vohra
`
`Efficacy of Porcine Versus Bovine Surfactants for
`Preterm Newborns With Respiratory Distress
`Syndrome: Systematic Review and Meta-analysis
`Neetu Singh, Kristy l. Haw/ey, Kristin Viswanathan
`
`\ drum.“ '
`
`Page 4 of 17
`
`This material was copied
`attha NLl'vl and may be
`Eu ti] a :t US: Copyright Laws
`
`American Academy of Pediatrics
`I)l{I)i(:/\'lll‘ll) TO THE HEALTH 0i" ALL CHILDRI‘ZN'
`
`Page 4 of 17
`
`

`

`PEDIATRIC?
`
`DECEMBER 2011- VOLUME 128 ~ NUMBER 6
`
`STATE-OF-THE-ART REVIEW ARTICLE
`
`Recent Advances in Management and Treatment of
`Hereditary Angioedema Niti Saraana, Timothy J. Craig
`
`SPECIAL ARTICLES
`
`® The Association of Acetaminophen and Asthma
`Prevalence and Severity John T. McBride
`
`® Contemporary Ethical Issues in Human Milk-Banking in
`the United States Donna J. Miracle, Kinga A. Szucs,
`Alexia M. Tcrke, Paul R. Helft
`
`1186
`
`Page 5 of 17
`
`lmmunogenicity and Safety of MMRV and PCV-7
`Administered Concomitantly in Healthy Children
`Michael leonardi, Kenneth Bromberg, Roger Baxter,
`Julie L Gardner, Stephanie Klopfer, Ouzama Nicholson,
`Michael Brock/ey, James Trammel, Vicky Leamy,
`Wendy Williams, Barbara Kuter, Florian Schc‘idel
`
`COMMENTARIES
`
`Reflections on US Immunization Challenges: Lady
`Montague, Where Are You? Edgar K. Marcuse
`
`e-commentaries—wwwpediatrics.0rg
`
`Safely Doing less: A Missing Component of the Patient
`Safety Dialogue Alan R. Schroeder, Stephen J. Harris,
`Thomas B. Newman
`
`Early Detection of Biliary Atresia Raises Questions
`About Etiology and Screening Ezequiel Neimark,
`Neal 8. leLeiko
`
`Pediatrics digest available online at
`www.pediatrics.org
`
`Emergency Department Laboratory Evaluations of Fever 1195
`Without Source in Children Aged 3 to 58 Months
`Alan E Simon, Susan L lukacs, Pauline Mendola
`
`National Trends in Exposure to and Experiences of
`Violence on the Internet Among Children
`Michele L Ybarra, Kimberly/J. Mitchell,
`Josephine D. Korchmaras
`
`American Academy of Pediatrics
`DEDICATED TO THE H IiAL'I‘H OI: ALI. CHILDREN" W
`
`Page 5 of 17
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`

`

`
`
`PEDIATRICS
`
`DECEMBER 2011 -VOLUME
`
`.
`
`‘F
`i
`- NUMBEP 3
`
`(it)
`
`1 196
`
`1 196
`
`L 7
`113
`
`1 197
`
`“93
`
`“98
`
`1 199
`
`1 199
`
`-
`On: Values Among Children and Adolescents Presenting
`to the Emergency Department Charlotte 8, Ilan 002ml ‘0”
`Jonathan N. Johnson, Nathaniel W. Taggal‘t [0’3 Th” e 5
`Michael J. Ackerman
`
`’
`
`.
`.
`Symptomatic Neonatal Arterial lschemlc Stroke. The
`International Pediatric Stroke Study Adam Kirtan,
`Jenn/fer Armstronnge/ls, Taeun Chang, Gabriel/e de Veber.
`Michael J, Rivkin, Marta Hernandez, Jessica Carpenter,
`Jerome Y. Yager, John K Lynch, Donna M. Ferriero, for the
`International Pediatric Stroke Study Investigators
`
`.
`changes in Body Mass During Elementary and Mlddle
`School in a National Cohort of Kindergarteners
`Ash/esha Datar, Victoria Shier, Roland Sturm
`
`llndernutrition, Poor Feeding Practices, and
`Low Coverage of Key Nutrition Interventions
`Chessa K. Latter, Bernadette M, E G, [Jae/mans,
`Mercedes de Unis, Monika T, Kothari, Marie T. Ruel,
`Mary Arimand, Megan Deitch/er, Kathryn G. Dewey,
`Monika Bless/tor, Elaine Borghi
`
`patients With Biliary Atresia Have Elevated Direct/
`Conjugated Bilirubin Levels Shortly After Birth
`San/iv Harpavat, Milton J. Finegold, Saul J. Karpen
`
`Attitudes Toward Newborn screening far
`Cytomegalovirus Infection Erica 8. Din, Cedric J. Brown.
`Scott D. Grosse, Chengbin Wang, Stephanie R. Bia/ek,
`Danielle S. Ross, Michael J. Cannon
`
`Pediatric Paradoxical Vocal-Fold Motion: Presentation
`and Natural History Stephen Mature, Courtney Hill,
`Glenn Bunting, Cathy Ba/iff, Jyoti Ramakrishna,
`Christina Scirica, Shannon Fracchia, Abigail Donovan,
`Christopher Hartnick
`
`Critically Ill Children During the 2009—2010 Influenza
`Pandemic in the United States Adrienne G, Randolph.
`Frances Vaughn, Ryan Sullivan, Lewis Robinson,
`8. Taylor Thompson, Grace Yoan, Elizabeth Smoot,
`Todd W. Rice, Laura L. taftis, Mark He/faer, Allan Doctor,
`Matthew Paden, Heidi Flori, Christopher Babbitt,
`Ana Lia Graciano, Rainer Gedeit, Ronald C. Sanders,
`John S, Giuliano, Jerry Zimmerman, Timothy M. Uyeki, and
`the Pediatric Acute Lung injury and Sepsis investigator’s
`Network and the National Heart, Lung, and Blood Institute
`ARDS Clinical Trials Network
`
`Antipsychotic Treatment Among Youth in Foster Care
`Susan dosRe/s, Yesel Yoon, David M. Rubin, Mark/l. Riddle,
`Elizabeth Noll, Aileen Rothbard
`
`1200
`
`A3
`
`Page 6 Of 17
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`This materialwas. :l:-
`
`ied
`
`American Academy of Pediatrics /
`i)lil)IC/\'l'ii1) TO THE H liAlfl'H ()i: ALI, CHILDREN"
`
`
`
`WW
`
`Page 6 of 17
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`

`PEDIATRICS”
`
`DECEMBER 2011 ' VOLUME 128 ' NUMBER 6
`
`Development of a Risk-Stratification Tool for Medical
`Child Abuse in Failure to Thrive Constance Mash,
`Thomas Frazier, Amy Nowacki, Sarah Worley,
`Johanna Co/dfarb
`
`Leveraging State Immunization Information Systems to
`Measure the Effectiveness of llotavirus Vaccine
`Margaret M, Cortese, Julie LeB/anc, Karen E. White,
`Robert C. Jerris, Patricia Stinchfield, Kenan L. Preston,
`James Meek, Lynda Odofin, Saadia Khlzer, Claudia A. Miller,
`Vicki Buttery, Slavica Mijatovic—Rustempasic, Jamie Lewis,
`Umesh D. Parashar, Lil/y Cheng lmmergluck
`
`Medical-Legal Partnership: Impact on Patients With
`Sickle Cell Disease Robert Pettignano, Sylvia B. Caley
`Lisa R. Bliss
`
`Parental Knowledge Regarding lifelong Congenital
`Cardiac Care Susan M. Fernandes, Amy Verstappen,
`Kathy Ackerman, Elizabeth E. Adams. Cheryl Barton,
`Petar Breitinger, Stephen Crumb, Kirsten Bummer,
`Kana Harada, Paul Khairy Michael J. Landzberg,
`Rachel Linstead-Coldsmiz‘h, Allison K. Meadows,
`Jo Ann Nieves, Arwa Said], Masato Takahashi, Jing Zhou,
`Sonja Ziniel, Roberta Williams, on behalf of the Adult
`Congenital Heart Association the Adult Congenital Cardiac
`Care Associate Research Network
`
`Page 7 of 17
`
`Clarithromycin in Preventing Bronchopulmonary
`Dysplasia in Ureaplasma urealyticum—Positive
`Preterm Infants Ramazan Ozdemir, Omer Erdeve,
`Evrim A/yamac Dizdar, Serife Sana Oguz, Nurdan Uras,
`Sibel Saygan, Erdem Karabulat, Ugur Dilmen
`Effect of Antihypotensive Treatment on Cerebral
`Oxygenation of Preterm Infants Without PDA
`Hilde J. C. Bonestroo. Petra M. A, Lemmers, Wim Baerts,
`Frank van Bel
`
`Ilse of a Visual Aid to Improve Counseling at the
`Threshold of Viability Venkatakrishna Kakki/aya,
`Lynn J. Groome, Daci Platt, Dalibor Kurepa, Arun Pramanik,
`Gloria Ca/dita, Lesley Conrad, Joseph A. Bocchini Jr,
`Terry C. Davis
`
`Preterm Milk Oligosaccharides During the First
`Month of Lactation Crazlo Gabriel/i, Lucia Zampini,
`Tiziana Ca/eazzi, Lucia Fade/la, Lucia Santaro, Chiara Pei/a,
`Francesca Giuliani, Enrico Bertino, Claudio Fabris,
`Giovanni V. Coppa
`
`Psychiatric and Medical Comorbidity and Quality of Life
`Outcomes in Childhood-Onset Epilepsy Christine B. Baca,
`Barbara C. Vickrey, Rochelle Cap/an, Stefanie D. Vassar,
`Anne I Berg
`
`'
`American Academy of Pediatrics
`DEDICA’I'ICD TO THE HliAlfl'H OF ALL CHILDREN" " ,
`
`Page 7 of 17
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`

`
`
`1205
`
`1207
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`1207
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`PEDIATRICS’Q
`
`DECEMBER 2011' VOLUME 128 ' NUMBER 8
`
`Parent Participation and Physician-Parent
`Communication During Informed Consent in Child
`Leukemia Melissa Cousino, Rebecoa Hazen,
`Amy Yamokoski, Victoria Miller, Stephen Zyzanski,
`Dennis Drotar, Eric Kodish, on behalf of the Multi-site
`Intervention Study to Improve Consent Research Team
`
`
`Implementing Medication Reconciliation in Outpatient
`Pediatrics David I. Rappaport, Brian Collins, Alex Kaster,
`Arnel Mercado, Jay Greenspan, Steven Lawless,
`Jobayer Hossain, lman Sharif
`
`Improving Reporting of Outpatient Pediatric Medical
`Errors Daniel R. Neuspiel, Erin H. Stubbs, Lori Liggin
`
`
`
`CASE REPORTS—wwwipediatricsorg
`
`
`
`Stress Hyperglycemia: A Sign of Familial Diabetes in
`Children fa/ Oran, Gal/a GateYab/onski, Liora Lazar,
`Moshe Phillip, Yael Gozlan
`
`Ductal Closure With Paracetamol: A Surprising New
`Approach to Patent Ductus Arteriosus Treatment
`Cathy Hammerman, Alana Bin-Nun, Einat Markov/ton,
`Michael S. Sch/mmel, Michael Kaplan, Daniel Fink
`
`Myocardial Infarction Associated With Use of the
`Synthetic Cannahinoid K2 Arshid Mir, Adebisi Ubafemi,
`Amy Young, Colin Kane
`
`Tricyclic Antidepressant Overdose in a Toddler Treated
`With Intravenous lipid Emulsion David Hendron,
`Gareth Menagh, Euan A Sand/lands, and Damian Soul/ion
`
`Treatment of Kimura Disease With Intravenous
`lmmunoglobulin Victor Hernandez~Bautista
`Marco Antonio Yamazaki—Nakashimada,
`Ruben Vazquez-Garcia, Danie/a Stamatelos—A/barran
`Daniel DarrascoeDaza, Ana Luisa Rodriguez-Lozano
`
`1208
`
`1208
`
`1208
`
`1209
`
`1209
`
`1209
`
`Cobalamin F Disease Detected by Newborn Screening
`and Follow-up on a Ida-Year-Old Patient 0lajumake Diadipa,
`David S. Rosenblat't, David Watkins, lsabelle Racine Miousse,
`Laurie Sprietsma, Dennis J. Dietzen, Marwan Shinawi
`
`
`
` eLetters———www.pediatricsorg eletters appear on page 1211 and online at
`
`www.pediatrics.org
`
`Errata
`
`1 2 1 2
`
`“2
`
`Page 8 Of 17
`
`Thismaterialwascopied
`atthe NLM and may be
`ELI b‘jEEt US Copyright Laws
`
`American Academy of Pediatrics
`DEDICA’I'EI) 'I'O ’I‘Hli H liAIIl'H OF r\I.l, CHILDREN"
`
`9
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`Page 8 of 17
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`
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`1219
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`1258
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`1210
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`1210
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`1210
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`1210
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`1210
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`1210
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`S215
`
`PEDIATRICS!”
`
`DECEMBER 2011 ' VOLUME128 - NUMBER 6
`
`FROM THE AMERICAN ACADEMY OF PEDIATRICS
`
`@ Policy Statement
`Meningococcal Conjugate Vaccines Policy Update:
`Booster Dose Recommendations Committee on infectious
`Diseases
`
`ifi
`
`policy Statement
`Health Care for Youth in the Juvenile Justice
`System Committee on Adolescence
`
`1m) Clinical Report
`Prevention and Management of Positional Skull
`Deformities in Infants domes laugh/in, Thomas G luerssen,
`Mark S. Dias, the Committee on Practice and Ambulatory
`Medicine, Section on Neurological Surgery
`
`e-policy pages—~www.pediatrics.org
`® Clinical Report
`Providing a Primary Care Medical Home for Children
`and Youth With Spina Bifida Robert Burke,
`Gregory S. Liptak, the Council on Children With Disabilities
`Clinical Report
`Male Adolescent Sexual and Reproductive Health
`Care Arik V. Marcell, Char/es Wibbelsman,
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`The Pediatrician’s Role in Family Support and Family
`support Programs oil/J, Fusse/l, Committee on Early
`Childhood, Adoption, and Dependent Care
`
`9 9
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`9(39
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`Expert Panel on Integrated Guidelines for
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`and Adolescents: Summary Report Roy—Ellen W. Kavey,
`Denise C. Simons-Morton, and Janet M. de Jesus,
`Supplement Editors
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`American Academy of Pediatrics
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`

`STATE-OF-THE-ART REVIEW ARTICLES
`
`
`
`Recent Advances in Management and Treatment of
`Hereditary Angicedema
`
`AUTHORS: Niti Sardana, MD,” and Timothy J. Craig, DO“
`
`"Department of Pediatrics, Weill Cornell Medical Center, New
`York Presbyterian Hospital, New York, New York; and “Division of
`Pulmonary, Allergy and Critical Care, Penn State University,
`Milton S. Hershey Medical Center, Hershey, Pennsylvania
`KEY WORDS
`hereditary angioedema, treatment, prophylaxis. Cl inhibitor,
`bradykinin
`ABBREVIATIONS
`HAE-hereditary arigioedema
`Cl-lNHv—Cl inhibitor
`SUP-#solvent detergentetrcated plasma
`FFP——fresh-frozen plasma
`
`TA
`tranexamic acid
`nfClrlNH—enanofiltered Ci inhibitor
`pdC17|NHfip|asma-dcrived C1 inhibitor
`rhCl~|Nlrlfirecombinant human Cl inhibitor
`FDA~—Food and Drug Administration
`
`Drs Sardana and Craig developed and worked on the
`manuscript and meet the requirements for being authors on the
`basis of substantial contribution to design of the study and the
`manuscript, drafting ofthe article and revising it as necessary,
`and approving the final version submitted; neither author is a
`government employee.
`
`wwwpediatricsorg/cgi/doi/10.1542/peds2011-0546
`
`doi:10.1542/peds201170546
`
`Accepted for publication Jun 8, 2011
`
`Address correspondence to Timothy J. Craig, DO, DIVISIOII of
`Pulmonary, Allergy and Critical Care, Penn State University, 500
`University Dr, 11041, Hershey, PA 17055. Email: tcraig@psu.edu
`PEDIATRICS (ISSN Numbers: Print, 0051-4005; Onlirie, 109874275).
`
`Copyright © 2011 by the American Academy of Pediatrics
`FINANCIAL DISCLOSURE: Dr Craig has performed research for
`L‘St Behring, Uyax, Pharming, Shire, Sai’inuin, and ViroPharma,
`speaks for ESL Behring, ViroPharma, and Dyax, and consults for
`USA Behring and Dyax. Dr Sardana has indicated she has no
`financial relationships relevant to this article to disclose.
`
`CONTEXT: Hereditary angioedema (HAE) is a rare autosomal-dominant
`disease characterized by recurrent self-limiting episodes of skin and
`mucosal edema Morbidity and mortality are significant, and new and
`pendingtherapies are now available to reduce the risk associated with
`the disease.
`
`OBJECTIVE: To update the reader on new advances in HAE to improve
`patient care.
`
`METHODS: We performed a literature search of Ovid, PubMed, and
`Google to develop this review, Articles that are necessary for the un-
`derstanding and use ofthe new therapeutic options for HAE were cho—
`sen, and studies of high quality were used to support the use ofther—
`apies, and in most cases, results from phase III studies were used,
`
`RESULTS: Until recently, therapy for HAE attacks in the United States
`consisted ofsymptom reliefwith narcotics, hydration, and fresh—frozen
`plasma, which contains active 01 inhibitor. Therapy to prevent HAE
`attacks has been confined to androgens and, occasionally, antifibrino-
`lytic agents; however, both drug groups have significant adverse ef-
`fects. The approval of Ct-inhibitor concentrate for prevention and
`acute therapy has improved efficacy and safety. Ecallantide has also
`been approved for therapy of attacks, and icatibant is expected to be
`approved in the next few months for attacks. Recombinant C'l inhibitor
`is presently in phase 111 studies and should be available for attacks in
`the near future.
`
`CONCLUSION: In this article we review the changing therapeutic op-
`tions available for patients in 2011 and beyond. Pediatrics 2011;128:
`11754180
`
`PEDlATRlCS Volume 128, Number 6, December 2011
`
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`The objective ofthis state-of-the-art re—
`
`HAE has similar clinical manifestations
`
`view is to update the pediatric physi-
`cian on recent and pending advances
`in the prevention and treatment of he-
`reditary angioedema (HAE) We focus
`mainly on therapeutic changes that
`have occurred over the past 5 years
`and are expected to occur in the next 2
`years.
`
`OVERVIEW
`
`HAE is characterized by self-limited tis-
`sue swelling that most often affects
`
`the skin and upper respiratory and
`gastrointestinal tracts. The prevalence
`ofHAE is estimated between i
`in 10 000
`
`and i
`
`in 150 000 worldwide, and the
`
`estimated population of people with
`HAE in the United States ranges from
`6000 to 10 000 people; however, we ex-
`
`pect that the number of patients with
`HAE is greater, Most data show no de-
`
`viation correlated to either gender or
`ethnicity. There is a significant age-
`related difference in frequency of HAE
`attacks (there is an increase at the
`
`time of puberty), but quality of life is
`affected significantly at all ages'v2
`
`The underlying cause of HAE is attrib4
`uted to autosomal-dominant
`inheri—
`
`tance of mutations in the Cl
`
`inhibitor
`
`(Ci-INH) gene (SERP/NGI), which was
`
`(i‘lqi2—
`mapped to chromosome ii
`qiStitMorethan 200 mutations ofthis
`gene have been linked to the clinical
`
`HAE manifestations.j The majority of
`the HAE cases show a familial pattern
`of inheritance, whereas 25% are re-
`
`lated to spontaneous mutations.
`
`Two types of HAE account for the ma—
`
`jority of cases. An estimated 85% of all
`
`patients have type i HAE, character-
`ized by low production of functionally
`active Ci-INH. The majority of patients
`with non—type ‘i HAE have type 2 HAE,
`characterized by normal or elevated
`levels of Ci~lNH but with functional im-
`
`pairment of the protein. Recently, a
`type 5 HAE (Mendelian Inheritance in
`Man No 610618) was described Type 5
`
`to the first 2 types but differs in that
`there are no abnormalities in C4 or Ci-
`lNH level or function. A mutation in co-
`
`agulation factor Xll protease (Hage—
`manfactor) with dominantinheritance
`
`is suspected to occur in some case of
`
`type 5 HAE, but causation has not been
`
`documented."H Type 5 HAE will not be
`discussed further in this review.
`
`Almost half of all patients with HAE
`manifest the disease before puberty
`The earliest onsets of HAE occur within
`
`the first year of life, and in 55% the
`
`disease presents between puberty and
`20 years of age/‘3 Another 15% develop
`
`their first episode later in young—adult
`life, and only ~4% of patients experi—
`ence their first attack after the age of
`40‘0,|O
`
`The number of attacks also varies
`
`among patients. Evidence indicates
`that patients with onset of symptoms
`before the age of 5 have attacks more
`frequently than those who develop HAE
`
`after 15 years of age.” In a study of 226
`patients with HAE,
`the frequency of
`yearly attacks varied; 50% experienced
`
`£5 per year, whereas 50% had >12
`attacks per year.8 The diagnosis of HAE
`is commonly delayedThe averagetime
`
`from the beginning of symptoms to di-
`agnosis ranges between 15 and 2i
`years” This delay results in signifi-
`cant morbidity and even mortality in
`affected patients. The knowledge of af—
`
`fected family members expedites rec-
`ognition ofthe disease.H
`
`Clinical presentation of HAE can in-
`volve any area of the skin, upper air—
`way, or abdomen. Almost all patients
`
`with HAE experience skin swelling. The
`
`disease commonly affects extremities
`butcantargetany body partand cause
`temporary debilitation and disfigure-
`ment that can last for up to 1 week.
`
`Facial edema might occasionally prog—
`
`ress to laryngeal swelling, which can
`be
`life-threatening and cause pro-
`
`longed intensive respiratory care or
`
`lNH (human protein derived from rab-
`
`1174
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`SARDANA and CRAIG
`
`Page 11 of17
`
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`even death from asphyxia.12 Laryngeal
`edema is most common in patients be-
`
`tween ll and 45 years of age.” Un-
`treated laryngeal edema usually pro—
`gresses for up to 8 to 12 hours and can
`last for up to 4 days. Patients with la—
`ryngeal edema might require urgent
`ventilator
`support
`and,
`therefore,
`
`should be observed in well-equipped
`facilities such as emergency depart-
`ments or lCUs.
`
`Abdominal HAE represents a different
`
`scope of medical and social problems
`for patients. Abdominal attacks can
`last for i to 8 days and often keep pa—
`tients on bed rest with a loss of pro
`ductive time. Children with abdominal
`
`attacks might require hospitalization.
`During abdominal attacks patients
`
`may experience significant pain,which
`might be misdiagnosed as a surgical
`
`emergency. Accordingly,
`abdominal
`more than one-third of patients with
`HAE have had their appendix removed
`
`or carry a history of exploratory
`laparoscopies.“
`
`ADVANCES
`
`Treating Patients With HAE
`
`Treatment options for HAE vary in
`terms of treatment for acute attacks.
`chronic therapy for patients with fre-
`
`quent attacks, and short-term prophyv
`lactic treatment before or during a
`known exposure to triggers such as in-
`fection,
`surgery, dental work, and
`trauma. According to the current 2010
`
`international consensus algorithm for
`
`the diagnosis, therapy, and manage—
`ment of HAE, supportive therapy com—
`bined with the specific therapies dis—
`
`cussed below is the preferred therapy
`for HAE attacks,M General measures
`
`for treating attacks involve hydration,
`pain relief, and treating as soon as
`possible with plasmaaderived Ci-INH
`(pdCi—INH) or ecallantide.
`It
`is antici—
`pated that icatibant (presently available
`in Europe) and recombinant human Ci-
`
`Page 11 of 17
`
`

`

`bits) (rhCl-INH) will soon be available in
`
`with attenuated androgens should be
`
`the United States as additional therapies
`
`monitored closely”?1 The major con-
`
`STATE~0F-THE-ART REVIEW ARTICLES
`
`erlands) produces Cl-INH concentrate
`in Europe under the trade name Cetor,
`and in the United States it is referred
`
`to as Cinryze (nfCl-lNH) (ViroPharma.
`Exton, PA). nfCl—INH is a nanofiltered,
`
`pasteurized Cl—lNH concentrate for in-
`travenous use. It has been approved by
`
`the US Food and Drug Administration
`(FDA) for adolescent and adult prophy-
`laxis at a dose of 1000 U every 5 to 4
`days; however,
`it has not been ap-
`proved
`for
`treatment
`of
`acute
`attacks?8
`
`The phase III study of nfCl-lNH per—
`formed for
`FDA approval
`demon»
`strated that it is effective as a prophy-
`
`lactic agent to reduce the number of
`attacks. The number of attacks was
`
`significantly reduced, but not elimi-
`nated, at a dose of 1000 U given every 5
`
`to 4 days by intravenous infusion. The
`approximate reduction in attacks was
`50%; however, the attacks that did occur
`in most cases were less severe and
`shorter in duration. Adverse events re-
`
`corded during the phase "1 study were
`minimalandthere were no recorded ep—
`
`isodes of anaphylaxis or seroconversion
`to HIV, hepatitis A, B, or C, or parvovirus.28
`These data led to FDA approval for nfCl-
`INH for prophylactic therapy at 1000 U
`twice per week; however, nfCl-lNH was
`not approved for the treatment of HAE
`attacks.
`
`A more recently approved Cl-INH con-
`
`(CSL
`(pdCl—INH)
`centrate, Berinert
`Behring, King of Prussia, PA), has been
`
`approved for use in acute attacks of
`HAE in the United States.25 It is a pas—
`
`teurized lyophilized human pdCl—INH
`
`concentrate. A phase III study of pdCl-
`lNH compared the efficacy of2 doses of
`the drug (10 and 20 U/kg) to that of
`
`placebo in 125 patients with HAE with
`abdominal or facial angioedema at—
`
`tacks. Compared with those who re-
`ceived placebo, subjects who received
`
`for attacks.
`available,
`
`If first-line drugs are not
`solvent
`detergent—treated
`
`plasma (SDP) or fresh—frozen plasma
`(FFP) may be used as
`second-line
`
`agents.“l
`
`lnfusion of FFP is effective for HAE at—
`tacksl‘i'f‘ Active Cl-lNH is one ofthe in-
`
`gredients in FFP, which replenishes
`the prot