- Email: [email protected]
What did the Task Force say?
www.jpeds.com
THE EDITORS’ PERSPECTIVES
September 2016 • Volume 176
We repair their hearts—but ignore their development — Reginald L. Washington, MD
What did the Task Force say? — Denise M. Goodman, MD, MS
© 2016 by Elsevier Inc.
T
he fields of Pediatric Cardiology and Pediatric Cardiac Surgery continue to successfully prolong the lives of children born with congenital heart disease (CHD). The medical home for these children usually centers on a primary care provider who has the responsibility for their overall health and well-being. Much has been learned regarding the neurodevelopment of these patients. In fact, specific guidelines have been published by the American Heart Association (2012) targeting the identification and management of developmental disorders in children with CHD. The goal of these guidelines was to optimize the care of children within their medical home by identifying those who are at the highest risk of developmental abnormalities. So how are we doing? In this volume of The Journal, Knutson et al show that an opportunity exists to improve the use of these guidelines in the primary care setting. The pediatric community is not aware of the American Heart Association’s guidelines and, therefore, does not use them as a tool to screen or refer children who would potentially benefit from testing and/or intervention. This report reviews barriers that inhibit the use of these guidelines, as well as presents easy suggestions that would facilitate putting the guidelines in the hands of primary care providers. Communication between the cardiology and the primary care communities needs to improve so that the overall well-being of these children is optimized. Article page 135 ▶
T
his volume of The Journal includes a Commentary on the recent recommendations of the US Preventive Services Task Force (USPSTF) (hereafter “the Task Force”) on universal screening for autism spectrum disorders. The authors give a comprehensive argument as to why they disagree with the Task Force’s recommendations, and why universal screening is warranted. To put this into context, it is useful to understand the charge and process of the Task Force, and how recommendations are graded. The Task Force was created in 1984 as an independent, volunteer expert panel in prevention and evidence-based medicine. The specific focus is to make recommendations on screening, counseling, and preventive medications, focusing only on people who have no signs or symptoms of the disease that the screening or intervention targets. The Task Force reviews existing studies, but does not conduct its own studies, and panel members are publically listed on the USPSTF web site, serving 4-year terms. After a topic is selected, a draft research plan is posted for public comment, and comments are incorporated into the final research plan. The Evidence-Based Practice Center then gathers, reviews, and analyzes evidence using the research plan as a road map, with the evidence summarized and graded. The draft recommendations and evidence review are also posted for public comment before final recommendations are made (http://www.uspreventiveservicestaskforce.org/, accessed May 31, 2016). The statement on screening for autism spectrum disorder in young children reads, “The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for autism spectrum disorder (ASD) in young children [aged 18-30 months] for whom no concerns of ASD have been raised by their parents or a clinician”, and was given an evidence grade of “I,” which means that “The 1
THE JOURNAL OF PEDIATRICS • www.jpeds.com USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.” The reader is prompted to read the clinical considerations section of the Recommendation Statement, with the conclusion, “If the service is offered, patients should understand the uncertainty about the balance of benefits and harms.” Echoing the Commentary, the clinical considerations sections acknowledges the benefits of early intervention; reiterates the burden of ASD on patients, families, and the healthcare system; recognizes that racial/ethnic and socioeconomic disparities exist with respect to diagnosis; and lists potential harms as principally related to misdiagnosis and anxiety pending confirmatory testing. So, where is the controversy? Unfortunately, to many readers, “we don’t know” is misinterpreted as “don’t perform screening.” Although public health has become regrettably politicized, the important message is that ASD is a significant public health concern, screening can easily be accomplished in a primary care setting, and we need sufficient behavioral health resources both to address concerns raised by preliminary screening and to perform early intervention in those for whom a diagnosis of ASD is confirmed. Article page 182 ▶
Why it is important to assess hypermobility in very young children — Philip J. Hashkes, MD, MSc
Genes and patent ductus arteriosus — Stephen R. Daniels, MD, PhD
2
H
ypermobility is associated with certain functional benefits (eg, sports and music), but with many potential deleterious consequences, some of which have been reported in previous volumes of The Journal. These include joint and muscle pain,“growinglike” pains, gastrointestinal symptoms, and even fibromyalgia, which can substantially impact the quality of life of affected children. A key potential consequence in younger children is developmental delay, particularly in gross motor milestones. Therefore, early detection of hypermobility is of importance. Prior to this study, objective diagnostic criteria were defined only in school aged and older children. Romeo et al adapted the most commonly used criteria, the Beighton score, for use in toddlers and preschool children. The major change they made was to substitute back flexion with ankle dorsiflexion, because it is difficult to request a very young children to perform a reliable back flexion. A surprising finding of the study was that the cutoff score the authors found to define hypermobility (>4) in their preschool cohort was similar to the accepted score in older children. Per clinical experience, it was expected that younger children would be much more flexible than older children. The results were confirmed in a group of children with syndromes associated with hypermobility. A limitation of this study is the need to prospectively follow these young children to observe changes in their flexibility as they grow. This study is a first step in defining hypermobility in very young children. Early screening for hypermobility may lead to greater vigilance in following developmental milestones and to early referral for physical therapy intervention, if needed. It also would be of interest to study whether early intervention may prevent some of the later deleterious consequences of hypermobility. Article page 162 ▶
T
he genetics of cardiovascular disease has been a confusing area, in part because our classification of cardiac morphology has not mapped well to genetic influences on cardiac development, but also because cardiac development is a very complex process involving many genes and environmental influences. In this volume of The Journal, Patel et al evaluate single nucleotide polymorphisms in candidate genes potentially associated with patent ductus arteriosus (PDA) in term infants. The candidate gene approach can be troublesome because it is often difficult to know which genes to pick. When results are negative, it is not always clear whether the wrong genes were chosen, the power was inadequate, or if there were other issues. When the results are positive, it is not always clear whether there is a causal relationship or whether significance (if not corrected) resulted from multiple statistical tests. (Continues on next page) Volume 176
THE EDITORS’ PERSPECTIVES In this case, Patel et al chose 17 genes, some of which were associated with syndromes with increased prevalence of PDA. Others were thought to be related to the physiology of PDA closure. They used two populations and accepted only results that were positive in both. They corrected for multiple comparisons. They found a gene in the transforming growth factor-beta pathway that met their criteria. Identification of this pathway may result in new approaches to prevent or treat PDA in term infants. Article page 57 ▶
Lymphocyte genetic diversity revealed by next generation sequencing — James F. Padbury, MD
Molecular testing increases detection of potential pathogens of acute gastroenteritis—now for the interpretation? — Sarah S. Long, MD
After the NICU: helping parents achieve the best outcomes — Robin H. Steinhorn, MD — Raye-Ann deRegnier, MD September 2016
I
n this volume of The Journal, Guo et al report studies designed to examine the sequence diversity of the CDR3 regions of T-cell receptor beta chain (TRB-CDR3) and immunoglobin heavy chain of circulating T and B cells. Studies were carried out with umbilical cord blood from newborns, pregnant women, and healthy adults. This tour de force review provides direct sequenced-based information on the diversity of the T cell receptors and immunoglobin heavy chains of circulating T and B cells. Remarkably, newborns had a distinctive repertoire that was independent of maternal immune status and showed greater variability. These are important reference data that provide insight into immune system development of newborns and possible implications for future studies using umbilical cord blood as a source of hematopoietic stem cells. Article page 69 ▶
T
here is no question that new capabilities in molecular diagnostic testing for infectious diseases have advanced clinical care tremendously. Ability to detect viruses and bacteria in normally sterile body sites, such as the central nervous system and bloodstream, are extremely helpful. Molecular methods also have advanced our understanding of pathogen-specific burdens of respiratory tract and other infections, a necessary first step in considering potential development of vaccines for prevention. In this volume of The Journal, Nicholson et al performed a robust prospective study in Davidson County, Tennessee, in children under 6 years of age with gastroenteritis. Stools were examined with polymerase chain reaction testing capable of detecting 21 possible pathogens—bacteria, viruses, and protozoa. They also tested stool samples of selected healthy subjects under 5 years of age at the time of a well-child visit as controls. Of 216 stool samples from children with acute gastroenteritis, 70% had a positive detection, norovirus genogroup II (36%) and Clostridium difficile toxin (16%) being most commonly identified. The findings that 71% of patients with C difficile toxin had an additional organism detected, 23% of patients overall had more than one pathogen detected, clinical characteristics did not differ whether none or >1 pathogen was detected, and 11% of 36 controls had a pathogen detected clearly led the investigators (and readers) to conclude that interpretation of the meaning of test positivity is tricky. Much additional study will be required to assist interpretation of positive tests. We have developed an understanding that recovery of bacteria in culture from mucosal or skin sites does not necessarily conclude pathogenicity, and in fact, we embrace the concept of a healthy microbiome. It will take time to sort out the meaning of a test with exquisite sensitivity from a specimen as complicated as a stool. Article page 50 ▶
C
ompared with children born at term, preterm infants are at greater risk for neurodevelopmental disabilities, including cerebral palsy, intellectual disabilities, and vision and hearing impairments. In its 2006 report, the Institute of Medicine estimated that in the US alone, costs associated with prematurity were more than $26.2 billion (http://www.nationalacademies.org/hmd/Reports/2006/Preterm-Birth-Causes -Consequences-and-Prevention.aspx, accessed July 8, 2016). Nearly one-third of this economic burden was due to sequelae of prematurity, including the need for special education and lost household and labor market productivity. This highlights the financial and human importance of research that improves the effectiveness of early 3
THE JOURNAL OF PEDIATRICS • www.jpeds.com intervention programs, and optimizes long-term neurocognitive and behavioral abilities in former premature infants. Early intervention programs have reported short-term efficacy in improving some cognitive outcomes for preterm infants, but less is known about the optimal timing and duration of interventions needed to achieve sustained improvement. Early interventions often target the child’s environment: Early childhood interactions with parents are known to be key influencers of brain structure and function, and unreliable adult responses during early childhood can disrupt brain architecture, as well as learning, behavior, and health. In this volume of The Journal, Flierman et al report results from a pilot study that extended the duration of a home-based, age-specific, parenting intervention by adding 4-6 extra home visits focused on parenting, between 18 and 22 months. These “booster” sessions were associated with improved outcomes in several areas of development as well as fewer behavioral problems, and high parent satisfaction. By teaching techniques of parental responsiveness, early intervention programs have the potential to reduce parental stress, anxiety, and depression, and optimize infant brain development after a stay in the neonatal intensive care unit. Because parenting and development are dynamic processes, it seems intuitive to extend such programs beyond early infancy. Yet, home visits will also be labor intensive and difficult to implement, and should be rigorously tested with larger, more diverse groups of preterm infants and their families. It also will be important to learn mechanistically how early intervention works to improve parent and child outcomes. With these data in hand, parent support programs that start in the neonatal intensive care unit could be extended longitudinally to make the most of our investment in neonatal intensive care. Article page 79 ▶
One small step in understanding the role that mobility limitations play in the obesogenic environment — Reginald L. Washington, MD
4
C
hildhood obesity remains one of the most serious issues facing children today. Many factors contribute to the obesogenic environment that children are exposed to on a daily basis. The most common factors include diet and nutrition, physical inactivity, screen time, and genetics. Less well known issues include poverty, education, culture, and geographic location. The battle to prevent and treat childhood obesity is ongoing and new information continues to be described. In this volume of The Journal, Wilson et al examined the physical activity participation, screen time habits, and the prevalence of overweight/obesity among children in the general population with mobility limitations and those enrolled in special education classes. They found that clear differences exist using the National Health and Nutrition Examination Survey database. The conclusions presented in this analysis need further study before generalized recommendations can be made. For example, the National Health and Nutrition Examination Survey database does not classify why a child is enrolled in special education or define the nature of the disability. Regardless, this study should serve as a springboard that eventually will add mobility status as a consideration when evaluating the obesogenic environment. Article page 23 ▶
Volume 176
THE EDITORS’ PERSPECTIVES
September 2016 • Volume 176
We repair their hearts—but ignore their development — Reginald L. Washington, MD
What did the Task Force say? — Denise M. Goodman, MD, MS
© 2016 by Elsevier Inc.
T
he fields of Pediatric Cardiology and Pediatric Cardiac Surgery continue to successfully prolong the lives of children born with congenital heart disease (CHD). The medical home for these children usually centers on a primary care provider who has the responsibility for their overall health and well-being. Much has been learned regarding the neurodevelopment of these patients. In fact, specific guidelines have been published by the American Heart Association (2012) targeting the identification and management of developmental disorders in children with CHD. The goal of these guidelines was to optimize the care of children within their medical home by identifying those who are at the highest risk of developmental abnormalities. So how are we doing? In this volume of The Journal, Knutson et al show that an opportunity exists to improve the use of these guidelines in the primary care setting. The pediatric community is not aware of the American Heart Association’s guidelines and, therefore, does not use them as a tool to screen or refer children who would potentially benefit from testing and/or intervention. This report reviews barriers that inhibit the use of these guidelines, as well as presents easy suggestions that would facilitate putting the guidelines in the hands of primary care providers. Communication between the cardiology and the primary care communities needs to improve so that the overall well-being of these children is optimized. Article page 135 ▶
T
his volume of The Journal includes a Commentary on the recent recommendations of the US Preventive Services Task Force (USPSTF) (hereafter “the Task Force”) on universal screening for autism spectrum disorders. The authors give a comprehensive argument as to why they disagree with the Task Force’s recommendations, and why universal screening is warranted. To put this into context, it is useful to understand the charge and process of the Task Force, and how recommendations are graded. The Task Force was created in 1984 as an independent, volunteer expert panel in prevention and evidence-based medicine. The specific focus is to make recommendations on screening, counseling, and preventive medications, focusing only on people who have no signs or symptoms of the disease that the screening or intervention targets. The Task Force reviews existing studies, but does not conduct its own studies, and panel members are publically listed on the USPSTF web site, serving 4-year terms. After a topic is selected, a draft research plan is posted for public comment, and comments are incorporated into the final research plan. The Evidence-Based Practice Center then gathers, reviews, and analyzes evidence using the research plan as a road map, with the evidence summarized and graded. The draft recommendations and evidence review are also posted for public comment before final recommendations are made (http://www.uspreventiveservicestaskforce.org/, accessed May 31, 2016). The statement on screening for autism spectrum disorder in young children reads, “The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for autism spectrum disorder (ASD) in young children [aged 18-30 months] for whom no concerns of ASD have been raised by their parents or a clinician”, and was given an evidence grade of “I,” which means that “The 1
THE JOURNAL OF PEDIATRICS • www.jpeds.com USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.” The reader is prompted to read the clinical considerations section of the Recommendation Statement, with the conclusion, “If the service is offered, patients should understand the uncertainty about the balance of benefits and harms.” Echoing the Commentary, the clinical considerations sections acknowledges the benefits of early intervention; reiterates the burden of ASD on patients, families, and the healthcare system; recognizes that racial/ethnic and socioeconomic disparities exist with respect to diagnosis; and lists potential harms as principally related to misdiagnosis and anxiety pending confirmatory testing. So, where is the controversy? Unfortunately, to many readers, “we don’t know” is misinterpreted as “don’t perform screening.” Although public health has become regrettably politicized, the important message is that ASD is a significant public health concern, screening can easily be accomplished in a primary care setting, and we need sufficient behavioral health resources both to address concerns raised by preliminary screening and to perform early intervention in those for whom a diagnosis of ASD is confirmed. Article page 182 ▶
Why it is important to assess hypermobility in very young children — Philip J. Hashkes, MD, MSc
Genes and patent ductus arteriosus — Stephen R. Daniels, MD, PhD
2
H
ypermobility is associated with certain functional benefits (eg, sports and music), but with many potential deleterious consequences, some of which have been reported in previous volumes of The Journal. These include joint and muscle pain,“growinglike” pains, gastrointestinal symptoms, and even fibromyalgia, which can substantially impact the quality of life of affected children. A key potential consequence in younger children is developmental delay, particularly in gross motor milestones. Therefore, early detection of hypermobility is of importance. Prior to this study, objective diagnostic criteria were defined only in school aged and older children. Romeo et al adapted the most commonly used criteria, the Beighton score, for use in toddlers and preschool children. The major change they made was to substitute back flexion with ankle dorsiflexion, because it is difficult to request a very young children to perform a reliable back flexion. A surprising finding of the study was that the cutoff score the authors found to define hypermobility (>4) in their preschool cohort was similar to the accepted score in older children. Per clinical experience, it was expected that younger children would be much more flexible than older children. The results were confirmed in a group of children with syndromes associated with hypermobility. A limitation of this study is the need to prospectively follow these young children to observe changes in their flexibility as they grow. This study is a first step in defining hypermobility in very young children. Early screening for hypermobility may lead to greater vigilance in following developmental milestones and to early referral for physical therapy intervention, if needed. It also would be of interest to study whether early intervention may prevent some of the later deleterious consequences of hypermobility. Article page 162 ▶
T
he genetics of cardiovascular disease has been a confusing area, in part because our classification of cardiac morphology has not mapped well to genetic influences on cardiac development, but also because cardiac development is a very complex process involving many genes and environmental influences. In this volume of The Journal, Patel et al evaluate single nucleotide polymorphisms in candidate genes potentially associated with patent ductus arteriosus (PDA) in term infants. The candidate gene approach can be troublesome because it is often difficult to know which genes to pick. When results are negative, it is not always clear whether the wrong genes were chosen, the power was inadequate, or if there were other issues. When the results are positive, it is not always clear whether there is a causal relationship or whether significance (if not corrected) resulted from multiple statistical tests. (Continues on next page) Volume 176
THE EDITORS’ PERSPECTIVES In this case, Patel et al chose 17 genes, some of which were associated with syndromes with increased prevalence of PDA. Others were thought to be related to the physiology of PDA closure. They used two populations and accepted only results that were positive in both. They corrected for multiple comparisons. They found a gene in the transforming growth factor-beta pathway that met their criteria. Identification of this pathway may result in new approaches to prevent or treat PDA in term infants. Article page 57 ▶
Lymphocyte genetic diversity revealed by next generation sequencing — James F. Padbury, MD
Molecular testing increases detection of potential pathogens of acute gastroenteritis—now for the interpretation? — Sarah S. Long, MD
After the NICU: helping parents achieve the best outcomes — Robin H. Steinhorn, MD — Raye-Ann deRegnier, MD September 2016
I
n this volume of The Journal, Guo et al report studies designed to examine the sequence diversity of the CDR3 regions of T-cell receptor beta chain (TRB-CDR3) and immunoglobin heavy chain of circulating T and B cells. Studies were carried out with umbilical cord blood from newborns, pregnant women, and healthy adults. This tour de force review provides direct sequenced-based information on the diversity of the T cell receptors and immunoglobin heavy chains of circulating T and B cells. Remarkably, newborns had a distinctive repertoire that was independent of maternal immune status and showed greater variability. These are important reference data that provide insight into immune system development of newborns and possible implications for future studies using umbilical cord blood as a source of hematopoietic stem cells. Article page 69 ▶
T
here is no question that new capabilities in molecular diagnostic testing for infectious diseases have advanced clinical care tremendously. Ability to detect viruses and bacteria in normally sterile body sites, such as the central nervous system and bloodstream, are extremely helpful. Molecular methods also have advanced our understanding of pathogen-specific burdens of respiratory tract and other infections, a necessary first step in considering potential development of vaccines for prevention. In this volume of The Journal, Nicholson et al performed a robust prospective study in Davidson County, Tennessee, in children under 6 years of age with gastroenteritis. Stools were examined with polymerase chain reaction testing capable of detecting 21 possible pathogens—bacteria, viruses, and protozoa. They also tested stool samples of selected healthy subjects under 5 years of age at the time of a well-child visit as controls. Of 216 stool samples from children with acute gastroenteritis, 70% had a positive detection, norovirus genogroup II (36%) and Clostridium difficile toxin (16%) being most commonly identified. The findings that 71% of patients with C difficile toxin had an additional organism detected, 23% of patients overall had more than one pathogen detected, clinical characteristics did not differ whether none or >1 pathogen was detected, and 11% of 36 controls had a pathogen detected clearly led the investigators (and readers) to conclude that interpretation of the meaning of test positivity is tricky. Much additional study will be required to assist interpretation of positive tests. We have developed an understanding that recovery of bacteria in culture from mucosal or skin sites does not necessarily conclude pathogenicity, and in fact, we embrace the concept of a healthy microbiome. It will take time to sort out the meaning of a test with exquisite sensitivity from a specimen as complicated as a stool. Article page 50 ▶
C
ompared with children born at term, preterm infants are at greater risk for neurodevelopmental disabilities, including cerebral palsy, intellectual disabilities, and vision and hearing impairments. In its 2006 report, the Institute of Medicine estimated that in the US alone, costs associated with prematurity were more than $26.2 billion (http://www.nationalacademies.org/hmd/Reports/2006/Preterm-Birth-Causes -Consequences-and-Prevention.aspx, accessed July 8, 2016). Nearly one-third of this economic burden was due to sequelae of prematurity, including the need for special education and lost household and labor market productivity. This highlights the financial and human importance of research that improves the effectiveness of early 3
THE JOURNAL OF PEDIATRICS • www.jpeds.com intervention programs, and optimizes long-term neurocognitive and behavioral abilities in former premature infants. Early intervention programs have reported short-term efficacy in improving some cognitive outcomes for preterm infants, but less is known about the optimal timing and duration of interventions needed to achieve sustained improvement. Early interventions often target the child’s environment: Early childhood interactions with parents are known to be key influencers of brain structure and function, and unreliable adult responses during early childhood can disrupt brain architecture, as well as learning, behavior, and health. In this volume of The Journal, Flierman et al report results from a pilot study that extended the duration of a home-based, age-specific, parenting intervention by adding 4-6 extra home visits focused on parenting, between 18 and 22 months. These “booster” sessions were associated with improved outcomes in several areas of development as well as fewer behavioral problems, and high parent satisfaction. By teaching techniques of parental responsiveness, early intervention programs have the potential to reduce parental stress, anxiety, and depression, and optimize infant brain development after a stay in the neonatal intensive care unit. Because parenting and development are dynamic processes, it seems intuitive to extend such programs beyond early infancy. Yet, home visits will also be labor intensive and difficult to implement, and should be rigorously tested with larger, more diverse groups of preterm infants and their families. It also will be important to learn mechanistically how early intervention works to improve parent and child outcomes. With these data in hand, parent support programs that start in the neonatal intensive care unit could be extended longitudinally to make the most of our investment in neonatal intensive care. Article page 79 ▶
One small step in understanding the role that mobility limitations play in the obesogenic environment — Reginald L. Washington, MD
4
C
hildhood obesity remains one of the most serious issues facing children today. Many factors contribute to the obesogenic environment that children are exposed to on a daily basis. The most common factors include diet and nutrition, physical inactivity, screen time, and genetics. Less well known issues include poverty, education, culture, and geographic location. The battle to prevent and treat childhood obesity is ongoing and new information continues to be described. In this volume of The Journal, Wilson et al examined the physical activity participation, screen time habits, and the prevalence of overweight/obesity among children in the general population with mobility limitations and those enrolled in special education classes. They found that clear differences exist using the National Health and Nutrition Examination Survey database. The conclusions presented in this analysis need further study before generalized recommendations can be made. For example, the National Health and Nutrition Examination Survey database does not classify why a child is enrolled in special education or define the nature of the disability. Regardless, this study should serve as a springboard that eventually will add mobility status as a consideration when evaluating the obesogenic environment. Article page 23 ▶
Volume 176