Led by Brooke Fridley, PhD, the BCB Core supports projects from initial concept through publication. The team assists with study design, hypothesis development, sample size estimation, statistical analysis, data visualization and dissemination of findings. By partnering with researchers throughout the research process, the BCB Core enables investigators to focus on clinical questions while leveraging advanced analytical expertise. 

The team also supports increasingly complex research initiatives involving large datasets, genomics and computational biology. In collaboration with the Research Informatics and Data Science team, BCB develops tools that help researchers better analyze and visualize study data, identify patterns and generate new hypotheses. These capabilities are particularly important as pediatric research continues to become more data intensive. 

In addition to project support, the BCB Core invests in workforce development through training programs, workshops and educational opportunities for investigators, fellows and junior faculty. Looking ahead, the team plans to expand its bioinformatics services, including support for whole genome sequencing and single-cell genomics, helping meet the growing analytical needs of translational pediatric research. 

Together, these efforts strengthen Children's Mercy's ability to translate research discoveries into innovations that improve the health and well-being of children.

The statement, “Update on Education for Families and Patients With Pediatric Heart Disease: A Focus on Technological Advancements, Procedures, and Transitions of Care,” was developed by nursing leaders and multidisciplinary complex care teams with extensive experience supporting children with congenital and acquired heart disease and their families. It synthesizes over a decade of emerging evidence on best practices for patient and family education across the care continuum, including procedural preparation, interstage monitoring, transitions of care, and the expanding role of digital health technologies.

The statement emphasizes a family-centered, trauma-informed approach to education and communication, underscoring the need to align clinical information with patient and caregiver understanding at each stage of care. It also highlights the critical role of interdisciplinary collaboration among cardiologists, nurses, psychologists, child life specialists, therapists, and social workers in supporting outcomes and long-term adjustment.

“Dr. Gross-Toalson and I have long shared a clinical focus on family-centered and trauma-informed care,” said Dr. Erickson, who chaired the writing group. “As we developed this updated statement, it was essential that these principles be explicitly incorporated into the evidence base.”

The original AHA statement on this topic was published in 2003. Work on the update began in early 2024. Following extensive peer review, the statement was approved through the AHA scientific review process in October 2025 and published online in March 2026.

Significance for Clinical Practice

AHA Scientific Statements are widely cited in peer-reviewed literature and are frequently used to inform clinical guidelines, grant applications, and health policy. They serve as expert consensus documents reflecting the current state of cardiovascular evidence.

“This paper provides a structured, evidence-based framework to guide cardiology providers in integrating education and well-being into clinical practice,” said Dr. Gross-Toalson. “Because cardiology appropriately emphasizes evidence-based care while tailoring decisions to individual patients, it was critical to apply that same rigor to education, communication, and family support.”

She added that families consistently identify communication with the care team as a key determinant of psychosocial adjustment. Standardizing and simplifying educational approaches—while remaining responsive to individual learning needs—may support improved long-term outcomes.

Notably, the authors extend beyond traditional educational recommendations, addressing how cognitive, emotional, developmental, and social factors influence how patients and families receive, process, and apply clinical information.

Additional perspective from Dr. Erickson is available in an accompanying AHA Science YouTube video.

Jacqelyn Nemechek, PhD, Hematology/Oncology/BMT, received a $250,000 grant for her project “Elucidating the Role of the Chromatin Reader ZMYND8 in Mediating Anti-Cancer Immunotherapy Through PD-L1.”

Read about Dr. Nemecheck's project

Taeju Park, PhD, Hematology/Oncology/BMT, received a $250,000 grant for his project “Inhibition of Glioblastoma Invasion Using CRK/CRKL-antagonist Peptides.”

Read about Dr. Park's project

Alexandra Prosser-Dombrowski, MD, Hematology/Oncology/BMT, received a $248,766 grant for her project “Defining Multi-omic Signatures of Developing and Established Infant Leukemia.”

Read about Dr. Prosser-Dombrowski's project

Laura Ramsey, PhD, Clinical Pharmacology and Toxicology, and Terrie Flatt, DO, MA, Hematology/Oncology/BMT, received a $250,000 grant for their project “Investigating Drug Metabolism in Hispanic Patients with Acute Lymphoblastic Leukemia.”

Read about Dr. Ramsey and Dr. Flatt's project

Jay Vivian, PhD, Clinical Genetics, received a $249,854 grant for his project “A Screen for Novel Small Molecules that Modulate Autophagy as a Therapy for Pediatric Leukemia.”

Read about Dr. Vivian's project

Vivekanand Yadav, PhD, Hematology/Oncology/BMT, received a $250,000 for his project “Novel Therapeutic Strategies for Diffuse Midline Glioma Using High-Throughput Combination Drug Screening.”

Read about Dr. Yadav's project

The Partners Advisory Board (PAB) is a collaboration between leadership teams from key MCA PAB member hospitals and research institutions. The PAB leverages regional strengths such as drug discovery and development and advancing cancer prevention, early detection, treatment, and survivorship to support and maintain KU Cancer Center’s National Cancer Institute comprehensive cancer center designation.

As Dr. Kyler explains, children with asthma and obesity have worse outcomes and poorer response to medications used to treat asthma symptoms, such as systemic corticosteroids (SCS), compared to lean children with asthma. Currently, the pharmacologic mechanisms underlying these differences and their associations with obesity aren’t well understood.

The goal of this study is to find out how having obesity affects how asthma medicine works in the body. To do this, Dr. Kyler and her team are comparing how the medicine moves through and affects the bodies of kids with asthma who have obesity and those with an average weight.

“It’s important to grow our understanding of obesity-related differences in inflammation and drug processing and response during asthma attacks. My hope is to improve steroid safety and response for these kids through obesity-focused dose optimization," said Dr. Kyler.

This K23 grant will support Dr. Kyler on her path to becoming an independent clinician scientist in the field of pharmacokinetic (PK) modeling and pharmacodynamic (PD) biomarker development for children with asthma and obesity.

Mentors on the study include Bridgette Jones, MD, MSCR, Clinical Pharmacology & Toxicology, and Elin Grundberg, PhD, Genomic Medicine Center.

“This work will position Dr. Kyler to become a leader in the field of precision therapeutics for children with asthma and obesity, able to link pharmacologic translational science to the bedside for performance of pediatric clinical trials,” said Dr. Jones and Dr. Grundberg.

In this new role, Dr. Wagner will lead the development of a world-class translational cardiovascular research program, building on the strengths of the Children’s Mercy Research Institute (CMRI) while exploring new opportunities for innovation and collaboration. His responsibilities include:

• Oversight and execution of all Heart Center research operations
• Mentorship and training of research staff and future cardiovascular scientists
• Building strategic partnerships with regional institutions (e.g., KUMC, Stowers Institute)
• Securing funding to ensure long-term program sustainability

 “I first came to Children’s Mercy as a third-year medical student rotating on the cardiology ‘Blue Team’ service. From that day forward, I was hooked and knew I wanted to become a Pediatric Cardiologist,” says Dr. Wagner, “Almost 20 years later, I am honored and humbled to cultivate another great program in the Heart Center that will improve the lives of our cardiac patients.”

Dr. Wagner’s vision includes establishing three distinct research tracks:

1. Exploratory and Pre-Clinical Research
2. Clinical and Diagnostic Trials
3. Cardiovascular Outcomes Research

About Dr. Wagner

Dr. Wagner is the Matson Family Endowed Professor in Cardiac Research and Professor of Pediatrics at the University of Missouri-Kansas City School of Medicine. He joined Children’s Mercy in 2013 and has served as Division Director of Clinical Pharmacology and Toxicology for more than five years. His research has significantly advanced the understanding of pharmacogenomics and precision medicine in pediatric cardiology.

He has led and contributed to numerous NIH-funded studies and national trials, including FUEL and FALD, and has received over $4.5 million in external funding. Dr. Wagner is also the principal investigator of the IMPROVE-FALD program and director of the Cardiology Pharmacogenomics Repository (CPR).

As Children’s Mercy Research Institute (CMRI) grows its research programs, the institute has welcomed many innovative, early-career investigators to its roster of researchers. These investigators bring their novel ideas, unique talents, and diverse interests to the CMRI. The following is a profile on one of the emerging principal investigators.

Ayanda Chakawa, PhD, Developmental and Behavioral Health, is both a clinical psychologist who provides behavioral health care to youth and a researcher interested in improving access to that care.

She is particularly interested in behavioral health care access issues for youth from historically marginalized populations. This includes those from Black, Indigenous, and People of Color (BIPOC) groups, socioeconomically disadvantaged backgrounds, and those from families with limited English language proficiency.  

Dr. Chakawa leads the ACCESS (Adolescent and Child Centered Engagement to Supports and Services) Behavioral Health Lab. The lab team studies how embedding behavioral health care into primary care clinics impacts access. They also study the impact that referring patients to other Children’s Mercy behavioral health clinics has on accessing care. In 2020, Dr. Chakawa, Leslee Belzer, PhD, Developmental & Behavioral Health, and Trista Perez Crawford, PhD, published an article based on their research supporting a multi-tiered integrated behavioral health care model to meet the needs of underserved sociodemographic groups. Dr. Chakawa, Dr. Belzer, Dr. Crawford, and Hung-Wen Yeh, PhD, Health Outcomes and Services Research, also published study results that indicated racial disparities in the use of telehealth for integrated primary care visits during COVID-19. Their research helped support a return to in-person integrated primary care clinical appointments.

PATHWAY project

Through her ACCESS Lab research and clinical experience at Children’s Mercy, Dr. Chakawa observed that many families faced challenges trying to navigate the behavioral health care system; this was even more pronounced for families whose child received a referral to another clinic for care. She wanted to address these challenges. In 2021, Dr. Chakawa received the Children’s Mercy Katharine Berry Richardson (KBR) award. With the KBR award funding, Dr. Chakawa began her research project, the PATHWAY (Promoting Access To Healthy Well-Being Across Youth) Behavioral Health Program, to address barriers to care by developing a culturally-relevant behavioral health care navigation model.

In 2022, Dr. Chakawa was named the first Diversity, Equity, and Inclusion (DEI) Scholar in the Children’s Mercy DEI Scholars Program. The goal of this program is to study the lack of diversity and inclusion in health care and the impact of health disparities on patients and families. Through the DEI Scholar award, Dr. Chakawa expanded research staffing for the PATHWAY program and engaged parent consultants as research partners to inform the development and implementation of the PATHWAY program. “The DEI Scholar award has provided increased protected time for me to research and build a clinical intervention that I’m passionate about,” said Dr. Chakawa. “I get to use my professional strengths to address a DEI-related public health crisis.”

The PATHWAY study involves piloting an individualized intervention to support families with behavioral health care navigation. Study participants are parents of youth referred to behavioral health services through primary care. The participants are from predominantly BIPOC and socioeconomically disadvantaged backgrounds and speak English or Spanish. The intervention follows participants for 13 months and includes surveys and care navigation check-ins. During the check-ins, the study team conducts motivational interviews to clarify referral information, help set goals to obtain care, and assess family confidence in meeting those goals. “This study has created space for families to explain and for us to assess what the actual barriers are. Then, we can address these barriers,” said Dr. Chakawa. “Patient-family education is a huge component in this process.”

Community engagement

From development to implementation, community engagement is the foundation for this study. Dr. Chakawa partners with community members from the Children’s Mercy Mental Health and Consejo de Familias Latinas y Hispanas Parent Family Advisory Councils (PFACs). In addition to the PFACs providing consultation, four parents from the PFACs form a designated community advisory board to the PATHWAY study. These parents include Emily Hamm and Jamila Weaver from the Mental Health PFAC and Brenda Quintana and Bertha “Alicia” Aldape from the Consejo de Familias Latinas y Hispanas PFAC. “The community members involved provide feedback at every phase of the study,” said Dr. Chakawa. “Their voices are there, and that is a critical component of our study.”

The community members bring their personal experience to the study. “Dr. Chakawa’s research sheds light on something families have known for so long - behavior health system navigation is challenging and complex,” shared the PATHWAY study community advisory board. “We love the collaborative effort that has gone into the project and the opportunity to be part of the change. We hope more research is on the horizon. If the PATHWAY project is any indication of where the direction of mental health care access is going, we know families of the future will be grateful for what we are doing today.”  

Trends

Although preliminary data is limited since the PATHWAY study is still ongoing, Dr. Chakawa has noticed some trends, including issues with system-level barriers like clinic paperwork requirements or communication issues that affect the navigation process. Another data trend is that social determinants of health impact both access to care and study engagement. These determinants include economic stability, education access, health care access, neighborhood environment, and social/community environment.

Dr. Chakawa’s long-term goal is to scale up the PATHWAY intervention to include more care navigation check-in opportunities for participants and to include staff dedicated to behavioral health care navigation throughout the health care system. She is applying for external grant funding to expand the study and its intervention.

In addition to her role at Children’s Mercy, Dr. Chakawa is an assistant professor at the University of Missouri-Kansas City School of Medicine. She joined Children’s Mercy in 2017 as an intern and then completed her fellowship in psychology in 2019. She received her PhD in clinical psychology from Auburn University, an MA in developmental psychology from the University of Alberta (Canada), and her BSc in psychology (with counseling emphasis) from Oakwood University, a historically black college/university in Huntsville, Alabama.

The funding is being used for their project, “ENTRY TRAC (Epilepsy and Neurology Transition Resources for Youth to Ready Adult Care)”. The goal is to create a patient- and family-centered transition program, strengthen the healthcare system's capacity to transition care effectively, and empower youth with epilepsy and special needs (YES) through a responsive feedback-driven improvement process.

As Drs. Abdelmoity and Le Pichon explain, transition of care (TOC) is the process by which youth are transitioned from pediatric to adult medicine. This process can be difficult for many youths and their families. This is especially true of those with complex medical needs, such as epilepsy and other special needs.

Epilepsy is one of the most common neurological disorders. Many of these children have special needs, including learning disabilities and other health issues. For these populations, TOC can be especially complex and traumatizing. While there are many organizations that assist with TOC, the process is fragmented, making it difficult for families to access care in a seamless and fluid way.

Drs. Abdelmoity, Le Pichon, and their team aim to develop a framework to support youth with epilepsy and special needs during TOC.

“Our goal is to create a framework that facilitates a smooth TOC process while addressing the diverse needs of both the youth and their families, encompassing medical, legal, societal, and emotional aspects,” said Drs. Abdelmoity and Le Pichon. “Acknowledging that many essential components are already in place but dispersed across various organizations at local, regional, and national levels, our proposed framework offers an integrated solution.”

It begins at the age of 13, marking the initiation of the transition process with a focus on education. This phase aims to equip youth and their families with the necessary knowledge and skills to navigate TOC effectively. Through tailored educational interventions, they will enhance their ability to articulate all needs, including diagnoses, medications, and social needs, thereby bolstering their self-efficacy. The legal learning skills will include applying for the least restrictive options for guardianship. Financial skills will address issues with medical insurance, employment, and other available governmental assistance. Societal skills target the ability to live independently.

“Affective skills are geared to prepare the family to enter the adult world, often requiring letting go of strong emotional bonds,” Drs. Abdelmoity and Le Pichon explain.

The second phase of the project involves implementation, taking place between the ages of 17 and 21, marking the actual physical transition to adult care. This crucial step hinges on a “warm hand-off,” ensuring a seamless transfer by facilitating at least one joint visit with both pediatric and adult providers present.

The final stage of the proposal focuses on ensuring sustainability. The overarching aim of establishing this framework is to create a model easily adaptable to other diseases and healthcare institutions. For widespread adoption, it is imperative to demonstrate its benefits for all stakeholders, including youth and their families, healthcare providers, and the medical system as a whole.

Additionally, it must be proven to be financially viable.

“This project has been meticulously designed with measures in place to objectively demonstrate the benefits across all affected levels. We aim to illustrate that implementing this TOC framework will not only benefit youth and their families but also enhance medical care in a fiscally responsible manner, ultimately contributing to the betterment of society as a whole,” said Drs Abdelmoity and Le Pichon.

Other team members on this project include Douglas Blowey, MD, Nephrology; Timothy Corden, MD, Research Learning Center; Emily Cramer, PhD, Health Services & Outcomes Research; Amanda Deacy, PhD, Gastroenterology; Erin Fecske, DNP, APRN, Neurology; Paul Glasier, PhD, Neurology; Luke Harris, MBA, Integrated Care Solutions; Stephanie Horton, Neurology; Gina Jones, DO, Neurology; Kadriye Lewis, Ed.D, Graduate Medical Education; Stephanie Pratt, LMSW, Social Work; Emily Thorpe, M.Ed., Office for Community Impact.

Please join us in congratulating Drs. Abdelmoity, Le Pichon, and their team!

Three Children’s Mercy Kansas City disciplines — neonatology, fetal cardiology and maternal fetal medicine — are collaborating with hospitals across North America to answer an important question: How does delayed umbilical cord clamping impact the neurodevelopment of babies with congenital heart disease (CHD)? 

Research has established that delaying cord clamping for 30 to 45 seconds or longer benefits both preterm and full-term newborns. Delayed cord clamping can: 

• Preserve the baby’s red blood cells. 
• Reduce the need for transfusions. 
• Improve iron levels, which reduces the risk of anemia and boosts brain development. 
• Decrease the risk of necrotizing enterocolitis. 
• Decrease the risk of brain bleeds. 
• Improve neurological and developmental outcomes. 

Newborns with CHD have been excluded from previous cord-clamping studies because of their complex health variables, including how blood volume affects newborns with cardiac issues.  “The reason they were excluded before is the reason we need the study now,” explained Laura Vricella, MD, FACOG, Medical Director of the Elizabeth J. Ferrell Fetal Health Center. 

“The already established benefits of delayed cord clamping may certainly be favorable to newborns with CHD,” said Maria Kiaffas, MD, PhD, Director of Fetal Cardiology, who outlined some of the hypotheses the study will be able to test.

 “Newborns with certain types of CHD (i.e. cyanotic) do benefit from a robust amount of red blood cells, and the ones that will need surgery may need less transfusions when they start with a good hematocrit. In addition, the decreased risk of necrotizing enterocolitis, a common complication in newborns with CHD, can favorably affect their morbidity and length of hospitalization.” 

“These kids are known to be at higher risk for neurological developmental issues,” said John Daniel, MD, MS, Neonatal ECMO Director. “The brain may receive less oxygen as a fetus in certain CHD types, and then newborns live in a persistently hypoxic state. They often go on cardiopulmonary bypass to have their operations. There are a lot of risk factors.” 

The new multi-site study, “CORD-CHD: Cord clamping among neonates with Congenital Heart Disease,” is led by Carl H. Backes, Jr., MD, from Nationwide Children’s, with Dr. Kiaffas and Dr. Daniel serving as site Principal Investigators at Children’s Mercy. The study is funded through the National Institutes of Health’s National Heart, Lung and Blood Institute. 

The study randomizes participating families into two groups: One where cords are cut after a delay of 30 to 60 seconds and one where cords are cut between 60 and 180 seconds following delivery. Patients will have neurodevelopmental follow-ups at 3-4 months, 9-12 months, and 22 to 26 months of age. The study will recruit participants for five years and run until 2030. With a total sample-size goal of 600, Children’s Mercy is tasked with enrolling 5 to 10 families per year. 

“We’ve sailed past our recruitment goals,” said Cheri Gauldin, BSN, CCRC, Senior Research Nurse Coordinator, Children's Mercy Research Institute. The team started recruiting participants in February and has already enrolled 11 families and completed 10 deliveries — the most of any participating site so far. 

When the team identifies a potential candidate (around 40% of the center’s deliveries have some form of CHD), they explain the study to the family at an interdisciplinary care meeting. Most families have been familiar with delayed cord clamping, either from previous births or by talking to their obstetricians, and have been eager to participate. 

“The Fetal Health Center has done an amazing job,” said Cheri. “They are being very proactive with helping us make sure everybody knows who’s enrolled.”  With the cooperation of today’s Fetal Health Center families, the innovative study will ensure future patients get the best evidence-based care possible. 

“This study wouldn’t be possible without the center,” agreed Dr. Daniel. “As our center continues to grow, we wanted to introduce research that bridges the gap between neonatology and maternal fetal medicine. This is a truly multidisciplinary study, and our Fetal Health Center is uniquely positioned to offer it to families.” 

Learn more about our Heart Center, Neonatology and Fetal Health Center at childrensmercy.org.

 

Dr. Amos’ “Combination Therapy in Adolescents to Treat Heavy Menstrual Bleeding-Review of Charts to Observe Treatment Patterns” (also called COMBATT HMB-RECON) project will collect treatment data for heavy menstrual bleeding in adolescent females with bleeding disorders. The study will evaluate the use of combined oral contraceptive pills and the medication tranexamic acid.

Although common, heavy menstrual bleeding in females can be a cause of emotional distress, adverse mental health outcomes and decreased quality of life. While oral contraceptives and tranexamic acid may be used either individually or in combination to treat the condition, there is no consensus on the standard of care and a lack of information on the effectiveness of the treatment approaches. In addition, safety concerns remain about the risk of blood clots when combining estrogen and tranexamic acid.

In her research study, Dr. Amos will evaluate the effectiveness of treating heavy menstrual bleeding in adolescents who have inherited bleeding disorders. She will also evaluate the safety of using oral contraceptives and tranexamic acid and the risk of blood clots, or thromboembolism.

“This retrospective study is the first step to providing much-needed evidence on the effectiveness of treating heavy menstrual bleeding with oral contraceptives and tranexamic acid to reduce first-line treatment failure and improve the mental health for girls with heavy menstrual bleeding and bleeding disorders,” says Dr. Amos.

Rangaraj Selvarangan, BVSc, PhD, director of Clinical Microbiology and Virology Laboratories, and director of Laboratory Medicine Research at Children’s Mercy, will lead the Emerging Infections AOE.

Dr. Selvarangan has nearly two decades of infectious disease research at Children’s Mercy. He has been the principal investigator of the Kansas City-New Vaccine Surveillance Network (KC-NVSN) team since 2009, which was recently awarded a five-year, $7.25 million grant from the Centers for Disease Control and Prevention to perform population-based, laboratory-confirmed, acute surveillance of acute gastroenteritis illness and acute respiratory illness in children. In addition, Dr. Selvarangan leads the multi-disciplinary COVID-19 Diagnostics and Investigations Empowering the Family (CODIEFY) study, which uses COVID-19 testing and single-cell genomic sequencing technology to create evidence-based COVID-19 education about the virus. Children’s Mercy is also one of the pediatric hospitals participating in the national Collaborative Long-term study of Outcomes for COVID-19 in Kids (CLoCk) consortium.

“As everyone is now well aware, viruses have the ability to significantly impact our lives - we’re more than two years into the pandemic and the virus continues to mutate and spread,” said Dr. Selvarangan. “The world’s experience with COVID-19 underscores the need for greater preparation by monitoring viruses in the community - the more prepared we are, the better we can handle any situation and the better we can help protect public health.”

The Emerging Infections AOE will focus on surveillance and outbreak investigations, pathogenesis of emergent infections, vaccine trials, industry-sponsored trials, emergency and pandemic preparedness, and support stewardship activities to make sure the right diagnostic test is done on the right patient, at the right time.

“There is a critical need to identify and prioritize which emerging infectious diseases pose the greatest risk to society,” said Tom Curran, PhD, FRS, Senior Vice President, Executive Director and Chief Scientific Officer. “We have already built a solid foundation and expanding this area of research will allow us to do even better surveillance and epidemiology, which will enhance our ability to handle any current or emerging situation.”

What makes the CMRI unique is the translational approach to research. The CMRI fosters an integrated research environment where no boundaries exist between science and medicine. Dr. Selvarangan noted a vast majority of his research has been done collaboratively with many other divisions and departments, which includes Infectious Diseases, Emergency Medicine, Laboratory Medicine, Genomic Medicine and Immunogenetics, Population Health, Neonatology, Adolescent Medicine, Nephrology, Gastroenterology and Precision Therapeutics.

“The research being done at Children’s Mercy touches multiple populations across our health system, and the collaborations between our research and clinical teams are vital when identifying new viruses or infection outbreaks,” said Rob Lane, MD, Executive Vice President, Physician-in-Chief. “This bench to bedside approach allows us to take results directly from the laboratory into the clinic to provide groundbreaking care for our patients.”

The other CMRI AOEs include:

• Genomic Medicine - The Genomic Medicine Center is one of the very few pediatric genome centers in the world carrying out clinical whole genome sequencing and single-cell genomics.
• Precision Therapeutics – Uses patient-specific information to optimize treatment for individual patients, which is supported by one of the largest pediatric clinical pharmacology programs in the nation.
• Population Health – Research focused on the communities we seek to help, and identifying the personal, social, economic, and environmental factors that influence the health of a child.
• Health Care Innovation – Identifies and advances products and processes that optimize the medical, surgical and therapeutic management of disease in children.

The CMRI was established in 2015 to accelerate precise diagnoses and treatments for complex childhood diseases and move kids to the forefront of research discoveries. The CMRI opened its new 9-story, 375,000 square-foot, pediatric research facility located on the hospital’s Adele Hall campus in the heart of downtown Kansas City in February 2021.

In addition, Dr. Selvarangan has also been appointed the William R. Brown Missouri Endowed Chair in Molecular Genetics and Molecular Medicine and will be formally invested at a ceremony this fall. His efforts as the Brown Endowed Chair in Molecular Genetics will be to build the research enterprise in molecular microbiology/virology with a focus on the newly created research area of emphasis in emerging infections.

Learn more about the Children’s Mercy Research Institute.

U.S. News Live Presents…

Webinar: Will Genetics and Genomics Deliver Precision Health?

In this webinar, leading experts discuss the latest on how widespread genetic screening programs can be incorporated into routine care, allowing patients to identify future risks and to develop more effective personalized approaches to treat disease or even to ward it off entirely.

Speakers include Dr. Tomi Pastinen, Director of the Genomic Medicine Center at the Children's Mercy Research Institute.

The Department of Orthopedic Surgery and Musculoskeletal Science at Children’s Mercy Kansas City performs approximately 100 surgeries to improve function for cerebral palsy patients each year, utilizing the single-event multilevel surgery (SEMLS) approach.

SEMLS incorporates several procedures into one surgical intervention. For example, bilateral proximal femoral varus derotational osteotomies are often combined with other lower extremity procedures. Doing so reduces the number of surgeries and hospitalizations for these patients, streamlining their postoperative care, reducing length of stay and helping patients advance to rehabilitation faster.

In pediatric hospitals where the team is highly skilled in SEMLS, outcomes have been very good and patient/family satisfaction superior.

Improving Pain Management for SEMLS Surgery

Epidural catheters are currently the gold standard when cerebral palsy patients undergo bilateral multilevel orthopedic surgery.

However, one of the challenges for those who receive an epidural is that it must remain in place postoperatively, usually for two days. This often requires the patient to be immobile, affecting the physiology of recovery, including lung function and mobility. A longer hospitalization also affects the family dynamic, requiring parents to take more time away from work or other caregiving responsibilities. Additionally, patients may have comorbidities that preclude epidural catheter placement.

This patient population also presents with additional medical challenges, including the fact that many are taking anti-spasmodics, may be on a baclofen pump, or may be on anti-epileptic medications.

To improve upon the patient’s experience, Kathryn Keeler, MD, Children’s Mercy Pediatric Orthopedic Surgeon, and Nichole Doyle, MD, Pediatric Anesthesiologist, collaborated to develop an Enhanced Recovery After Surgery (ERAS) protocol.

ERAS Protocol for SEMLS Patients

The ERAS protocol Dr. Doyle and Dr. Keeler developed is used for cerebral palsy patients undergoing bilateral lower extremity surgeries. 
Key elements of the protocol include:

• Use of peripheral nerve blocks instead of epidural catheters.
• Earlier mobilization of patients, with an earlier start to physical therapy.
• Discontinued use of the Foley catheter before arrival to the post-anesthesia care unit.
• Use of dexmedetomidine infusion for the first postoperative day as part of a multimodal pain management plan.

To determine the effectiveness of the protocol, they performed a pilot study of 10 consecutive cerebral palsy patients undergoing bilateral lower extremity surgery from May to July 2020, comparing them with 10 controls from 2017 to 2019. The groups were matched by Gross Motor Function Classification System (GMFCS) score, procedure performed and age. The biggest difference between the two groups was in the type of pain control used. The control group received epidural catheters.

The ERAS group received peripheral nerve blocks in the operating room with clonidine or dexamethasone added to prolong the blocks based on the surgical procedures planned.

Preoperatively patients were counseled about the protocol and what to expect. Some high-risk patients were started on gabapentin at this visit. On the day of surgery families were instructed to continue clear liquids until two hours before surgery. If gabapentin was not started at the preop visit, patients were given a dose preoperatively.

Intraoperatively, the ERAS patients received intravenous (IV) acetaminophen and ketorolac. They also had intraoperative dexmedetomidine and/or ketamine infusions. A short-acting narcotic was given as needed.

At completion of the surgery the Foley catheter was removed. Upon transfer to the floor, the patients continued on a dexmedetomidine infusion 0.1 mcg/kg/hr-0.2mcg/kg/hour and they were placed on scheduled acetaminophen, ketorolac, gabapentin and a bowel regimen. They received valium, narcotic, ondansetron and diphenhydramine as needed. If needed, a PCA/NCA was started.

Key Outcomes

This pilot study showed that following an ERAS protocol can help minimize the variation of care and enhance the patient and family experience with bilateral lower extremity surgery. Results showed a decreased length of stay of almost a full day and a reduction in postoperative narcotic consumption for the ERAS group. Side effects such as nausea, vomiting and pruritus also decreased in the ERAS patients.

Overall, performing single-shot peripheral nerve blocks at the beginning of the surgery has the potential to substantially increase the value of care delivered to this complex patient population, but further study in a larger patient population is needed to confirm results.

ERAS Pilot Study Highlights

• 10 ERAS protocol patients; 10 control group patients.
• GMFCS 4 for both groups.
• Decreased postoperative narcotic use in ERAS group to 0.12 morphine equivalents/kg per day compared to 0.19 morphine equivalents/kg in control group.
• Postoperative need for a PCA/NCA pump was zero in the ERAS group compared to four in the control group, two of which occurred after discontinuation of the epidural catheter.
• Time to postoperative discharge from physical therapy was 1.70 days in the ERAS group versus 2.44 days in the control group.
• Hospital length of stay was 2.20 days for the ERAS group versus 3.0 days in the control group.

Collaborate with us to study the ERAS protocol

Children’s Mercy is seeking to study the ERAS protocol in a larger patient population by collaborating with other pediatric institutions performing single-event multilevel surgeries for cerebral palsy patients. To work with our team, contact:

Kathryn Keeler, MD, Pediatric Orthopedic Surgeon 
kkeeler@cmh.edu

(816) 234-3696

Nichole Doyle, MD, Pediatric Anesthesiology 
nmdoyle@cmh.edu

(816) 234-3464

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

Reference:

1. Schendel DE, et al. (n.d.). Public Health Issues Related to Infection in Pregnancy and Cerebral Palsy. PubMed - NCBI. National Center for Biotechnology Information. Retrieved 9/18/2020 from: https://www.ncbi.nlm.nih.gov/pubmed/11921385.

Following the Methodology of CAR-T Cell Therapies 

Tregs are rare cells in the blood of healthy patients. Only 1%-2% of T cells are Treg in the blood of healthy patients. This is usually fine, as conventional T cells help us fight infection and other stressors. However, in certain conditions, the activity of the conventional T cells is insufficiently controlled by Tregs, and help is needed. 

In 2013, the team began examining the basis of CAR-T cell therapies for the treatment of leukemia and lymphoma. This technology is now well known and is used to transform T cells into cancer-specific killer cells. Dr. Fischer and the team wanted to turn this idea on its head and determine if it would be possible to teach T cells to “act” more like Tregs. Instead of killing targets, could these engineered Tregs go to areas of inflammation and reduce the activity of the immune system? In conditions where there is an abundance of inflammation or a genetic condition where patients are not producing enough Tregs, the team knew that increasing the number of Tregs could halt unwanted inflammation. The research team began exploring the possibility of engineering Tregs out of normal T cells. 

Success in Mouse Model with Graft-Versus-Host Disease  

While Treg cells have been extensively studied in recent years, this research represents a new way of thinking. Previously, efforts had been made to overexpress forkhead box P3 (FOXP3) factor within T cells — which has shown some limited success in controlling inflammation. But the researchers found improved results by adding the specialized transcription factor Helios (Ikzf2) from the Ikaros Zinc Finger (IkZF) family that regulates the hematopoietic cell development, including that of CD4+ T cells. The team engineered conventional human T cells to express both Helios and FOXP3 transcription factors and become “engineered Tregs.” They infused the altered cells into a mouse model of graft-versus-host disease, where a mouse without its own immune system is given human immune cells. This model reflects the unwanted immune activity that happens when patients receive a stem cell transplant and the donated cells begin attacking the recipient. The team was able to show that their modified T cells suppressed inflammation in mice like Tregs. This resulted in increased survival of the affected mice, thus becoming the first group to use Helios to improve the clinical function of engineered Tregs. 

Years of Research Resulted in Patent 

The work of Drs. Fischer and Markiewicz is the culmination of work that began several years ago with financial support from the Tripp family, who have worked with Children’s Mercy following the liver transplant of Brendan Elam Tripp in 2012. Dr. Fischer originally began the research with Thomas M. Yankee, PharmD, PhD, a Professor of Microbiology, Medical Genetics and Immunology at The University of Kansas Medical Center. Unfortunately, Dr. Yankee passed away from cancer in 2017. Following his passing, his colleagues continued their efforts to develop anti-cancer immunotherapy and immunomodulatory therapy for use in disordered inflammation. Dr. Markiewicz continued the work with Dr. Fischer and assumed the role as the principal investigator on the study. 

Critical to the success of continuing the research will be partnerships with industries. The team worked with Marcia Molina, Director of Technology Transfer and Commercialization in the Children’s Mercy Center for Pediatric Innovation, who facilitated the patent of the technology and the license with a biotech company in the summer of 2021. In November 2021, the team received three additional years of funding from Children’s Mercy to continue the research. They have also submitted a grant to the Juvenile Diabetes Research Foundation and are exploring the option to get federal funding in the future. 

Envisioning a Cell-based Therapy, Medication-Free Survival Following Transplants 

Dr. Fischer developed an early interest in this field of study and sparked his love for the translational sciences during his pediatric residency and fellowships, working in the lab of Angus W. Thomson, PhD DSc, at the University of Pittsburgh. Dr. Thomson works with dendritic cell therapy with the intent to do the same thing — create a more tolerant environment and prevent the rejection of organs. 

Currently, patients who undergo treatment following an organ transplant require daily medication to prevent the liver from being rejected by conventional, inflammatory T cells. The goal of this research is to engineer cells that allow the patient’s own immune system to take care of the liver and prevent inflammation. This could mean medication-free survival of patients who receive a transplant. In patients with autoimmune diseases like Type 1 diabetes or other conditions with unwanted inflammation, this biologic therapeutic could “teach” the immune system to protect the organ system or systems being attacked. Ultimately, Dr. Fischer hopes to bring this cell-based therapy to pediatric patients using the resources, creativity and cutting-edge scientific support of the Children’s Mercy Research Institute. 

Learn more about Gastroenterology research at Children's Mercy 

Ryan Fischer, MD, Chief, Section of Hepatology & Transplantation; Director, Liver Care Center; Medical Director, Liver Transplant 

rtfischer@cmh.edu

(816) 234-3066 

References:

1. Głowińska-Olszewska B, Szabłowski M, Panas P, et al. Increasing co-occurrence of additional autoimmune disorders at diabetes Type 1 onset among children and adolescents diagnosed in years 2010-2018—single-center study. Front Endocrinol. Published online August 6, 2020. doi:10.3389/fendo.2020.00476 

2. Centers for Disease Control National Diabetes Statistics Report — Centers for Disease Control and Prevention. National Diabetes Statistics Report website. https://www.cdc.gov/diabetes/data/statistics-report/index.html. Accessed [date]. 

3. Kwong AJ, Kim WR, Lake JR, Smith JM, Schladt DP, Skeans MA, Noreen SM, Foutz J, Booker SE, Cafarella M, Snyder JJ, Israni AK, Kasiske BL. OPTN/SRTR 2019 Annual Data Report: Liver. Am J Transplant. 2021 Feb;21 Suppl 2:208-315. doi: 10.1111/ajt.16494. PMID: 33595192.

In recent years there have been marked improvements in survival and outcomes for infants born at less than 30 weeks of gestational age.¹ Despite this positive trend, children born very preterm (VPT) remain at high risk for long-term physical and mental health problems, as well as developmental delays. In longitudinal follow-up studies, VPT children have shown deficits or delays in cognitive, motor and language development and are at increased risk for disorders such as cerebral palsy and autism spectrum disorder.^2-6

However, most studies examining neurodevelopmental outcomes in VPT children report rates of impairment for individual outcomes separately, when in fact it is more likely some outcomes co-occur. An alternative to this approach is to integrate across multiple measures to identify subgroups of children with similar neuroatypical patterns of behavior.

NOVI Studies VPT Infants

The Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) multicenter study enrolled infants born at less than 30 weeks of postmenstrual age (PMA) from nine NICUs affiliated with six universities located throughout the country from April 2014 to June 2016. The regional diversity and volume of patients enrolled are strengths of the NOVI study. Often research into VPT patient outcomes has been limited to single-center studies.

Another unique aspect of the NOVI study is that it not only concerns neonatal-perinatal risk, but the environment of raising the child, exposure to environmental modulators and the frequency and severity of any illness or developmental impairments, as well as therapeutic services utilized.

The Level IV Neonatal Intensive Care Unit at Children’s Mercy Kansas City is one of the sites that originally enrolled VPT infants in this project and continues to follow them to 7 years of age. Brian Carter, MD, Children’s Mercy Neonatologist and Bioethicist, serves as the site’s principal investigator.

Neurodevelopmental Profiles of VPT Infants at 2 Years of Age

The researchers involved in the NOVI study have begun analyzing data gathered from 587 infants born at less than 30 weeks of PMA from the participating sites. To date, they have authored several notable papers, including one recently published online in Pediatric Research that addresses the neurodevelopmental profiles of infants born at less than 30 weeks of gestation at 2 years of age.⁷

Their objective was to describe neurodevelopmental profiles of these children using cognitive, language, motor and behavioral characteristics. Age 2 outcomes included Bayley-III subscale scores, Child Behavior Checklist syndrome scores, diagnosis of cerebral palsy, and positive screen for autism spectrum disorder risk. They used latent profile analysis to group children into mutually exclusive profiles.

What the researchers found were four discrete neurodevelopmental profiles indicating distinct combinations of developmental and behavioral outcomes.

• Two of the profiles included 72.7% of the sample, with most having Bayley scores within the normal range. 
• The other two profiles included the remaining 27.3% of the sample, with most having Bayley scores outside the normal range. Only one profile (11% of sample) comprised children with elevated behavioral problems. These children are most at risk for adverse outcomes. 

While there are additional findings within each profile, this study illustrates the need to move beyond individual variable analysis and toward novel approaches to study different risk profiles in this patient population.

How “Child-Centered" Assessments Could Help VPT Infants

The researchers concluded that “child-centered” analysis techniques may provide clinically useful information and could facilitate the development of targeted intervention strategies for VPT children.

For example, relatively few NICUs across the nation routinely conduct the NICU Network Neurobehavioral Scale (NNNS) assessment before a VPT infant is discharged. This assessment is a valid biomarker for detecting at-risk infants and predicting their outcomes. Results could help identify infants in greatest need for enhanced surveillance in NICU follow-up clinics and determine which infants may benefit most from rapid enrollment in early intervention services, giving them the opportunity for the best possible outcome.

This type of universal screening is consistent with the American Academy of Pediatrics^8,9 promotion of universal screening for a wide range of neurodevelopmental and behavioral conditions that impact children’s long-term developmental and achievement potential and the provision of early intervention referral for high-risk children, even in the absence of a specific diagnosis.

The researchers anticipate additional publications and insights into this important issue as the data collected from this project is further analyzed and published.

Learn more about the Division of Neonatology at Children's Mercy

Brian Carter, MD, Neonatologist; Bioethicist and Co-Director, Pediatric Bioethics Certificate Course, Children’s Mercy Kansas City 

bscarter@cmh.edu

 (816) 731-7028 

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

References:

1. Glass HC, Costarino AT, Stayer SA, Brett CM, Cladis F, Davis PJ. Outcomes for extremely premature infants. Anesth Analg. 2015;120(6):1337–1351. doi:10.1213/ANE.0000000000000705

2. Aarnoudse-Moens CSH, Weisglas-Kuperus N, van Goudoever JB, Oosterlaan J. Meta-analysis of neurobehavioral outcomes in very preterm and/or very low birth weight children. Pediatrics. 2009;124(2):717–728. doi:10.1542/peds.2008-2816

3. Stephens BE, Vohr BR. Neurodevelopmental outcome of the premature infant. Pediatr Clin North Am. 2009;56(3):631–646. doi:10.1016/j.pcl.2009.03.005

4. Allen MC. Neurodevelopmental outcomes of preterm infants. Curr Opin Neurol. 2008;21(2):123–128. doi:10.1097/WCO.0b013e3282f88bb4

5. Vohr BR, Wright LL, Poole WK, McDonald SA. Neurodevelopmental outcomes of extremely low birth weight infants <32 weeks’ gestation between 1993 and 1998. Pediatrics. 2005;116(3):635–643. doi:10.1542/peds.2004-2247

6. Agrawal S, Rao SC, Bulsara MK, Patole SK. Prevalence of autism spectrum disorder in preterm infants: a meta-analysis. Pediatrics. 2018;142(3):e20180134. doi:10.1542/peds.2018-0134

7. Camerota M, McGowan EC, Hofheimer JA, et al. Neurodevelopmental profiles of infants born <30 weeks gestation at 2 years of age. Pediatric Res. Published online December 9, 2021. doi:10.1038/s41390-021-01871-2

8. Lipkin PH, Macias MM; Council on Children with Disabilities, Section on Developmental and Behavioral Pediatrics. Promoting optimal development: identifying infants and young children with developmental disorders through developmental surveillance and screening. Pediatrics. 2020;145(1):e20193449. doi:10.1542/peds.2019-3449

9. Council on Children with Disabilities; Section on Developmental Behavioral Pediatrics; Bright Futures Steering Committee; Medical Home Initiatives for Children with Special Needs Project Advisory Committee. Identifying infants and young children with developmental disorders in the medical home: an algorithm for developmental surveillance and screening. Pediatrics. 2006;118(1):405–420. doi:10.1542/peds.2006-1231

Participating Centers:

1. Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI

2. Department of Pediatrics, Women & Infants Hospital, Providence, RI

3. Department of Pediatrics, Warren Alpert Medical School of Brown University, Providence, RI

4. Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC

5. Department of Pediatrics-Neonatology, Children’s Mercy Kansas City

6. Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC

7. Department of Pediatrics, University of Hawaii John A. Burns School of Medicine, Honolulu, HI

8. Department of Pediatrics, Spectrum Health-Helen DeVos Hospital, Grand Rapids, MI

9. Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA

In research published Nov. 1, 2021, in Children,¹ Dr. Friesen and team sought to assess cost variability in the care of AP-FGIDs across health systems, races, and specific AP-FGID diagnoses. Using the Cerner Health Facts^® database, Dr. Friesen identified 17,287 encounters, of which 38.7% had total cost data available. Statistical analysis of those encounters revealed considerable variation in costs both within and across health care systems. Variability by race/ethnicity was also significant, with generally higher costs for Hispanics and lower costs for Native Americans.

Unfortunately, while the database provides total encounter costs, costs for specific tests or treatments were not widely available and thus what drives the costs could not be discerned. Also significant, the database does not allow reliable assessment of treatment outcomes, which is key in understanding the value of different treatment options. Though there is a goal to disrupt the pattern of rising costs, Dr. Friesen emphasizes that cost alone cannot determine value. Higher short-term costs are not inherently bad if they provide better outcomes for the patient. With this research, Dr. Friesen is aiming to change the conversation from decreasing cost to increasing value and consideration of outcomes in the decision-making process.

Shifting Care Locations From Emergency Departments to Clinics

In a second study, Dr. Friesen focused primarily on determining patterns of care locations for pediatric AP-FGID patients, as well as how gender and race affected those location patterns.² A secondary aim was to investigate the cost variability within the emergency department (ED). This project also used the Cerner Health Facts^® database to identify 53,750 patients between the ages of 8 and 17 for assessment. Dr. Friesen’s team concluded that the emergency department was the most common location for care, and often the only location for Hispanic and African American patients.

To Dr. Friesen, this data suggests the existence of barriers to outpatient clinic access and/or affordability for nonwhite or low-income patients, some of which could be addressed on an individual level when ED care providers refer patients to outpatient clinics. He acknowledges that some issues, such as treatment cost, transportation cost or neighborhood safety, cannot be resolved at the hospital level. Further study is needed to gather sufficient data to garner support for multidisciplinary clinics at institutional or even national levels.

Shifting treatment location from the ED to an outpatient setting is critical not only for managing costs but also for providing more thorough evaluation and care. Patients with AP-FGIDs typically have a variety of psychosocial issues, such as anxiety, depression or sleep disturbances. One of Dr. Friesen’s goals with this research is to develop additional resources for ED personnel, to educate them on the need and pathway for referring patients to clinics.

Dr. Friesen notes that treating abdominal pain can be complicated. For most patients, symptoms do not get better with medicine alone. The associated psychosocial issues must be addressed, which cannot take place in an ED setting. Care needs to be provided in a multidisciplinary clinic with planned care across all aspects of the illness.

Conclusions

Both studies indicate sufficient variability in care models and costs to support future multisite studies on the value of specific tests and treatments. Such research could lead to the development of guidelines for evaluation and treatment of AP-FGIDs, which could improve patient outcomes while also reducing costs.

Dr. Friesen concludes that treatment costs for this disease are significantly higher than necessary, and that they are directly influenced by patterns of care. Thus, the target for future research involves analyzing how to improve outcomes, lower costs, and therefore maximize value.

Learn more about pediatric abdominal pain at Children's Mercy

Craig Friesen, MD, Medical Director, Abdominal Pain Program

cfriesen@cmh.edu

(816) 234-3066

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

References:

1. Livitz M, Friesen AS, Glynn EF, Schurman JV, Colombo JM, Friesen CA. Healthcare system-to-system cost variability in the care of pediatric abdominal pain-associated functional gastrointestinal disorders. Children (Basel). 2021;8(11):985. Published 2021 Nov 1. doi:10.3390/children8110985

2. Friesen AS, Livitz M, Glynn EF, Schurman JV, Colombo JM, Friesen CA. High rate of emergency department care in youth with abdominal pain–associated functional gastrointestinal disorders. Pediatr Emerg Care. Published online January 27, 2022. doi:10.1097/PEC.0000000000002647

Almost 1 in 13 American children (7.6%) have IgE-mediated food allergies (FA). The standard treatment for FA is avoiding allergenic foods, but alternative items can be hard to find and afford. Around 21% of children with FA also experience food insecurity (FI), or a household’s inability to acquire food due to lack of money or resources.

FI disproportionately affects Latinx, Native American and Black communities and has been rising during the pandemic. The impacts of FI on children include higher rates of asthma, obesity, academic trouble, behavior issues, anxiety, depression and more. The combination of FA and FI is dangerous: Children with both FI and FA are at greater risk of anaphylaxis than are their peers.

Shroba Heads AAAAI Food Insecurity Work Group

Because of the increase in FI, the American Academy of Allergy, Asthma and Immunology (AAAAI) FI Work Group surveyed allergists’ FI knowledge and practices. The survey report was published January 2022 in The Journal of Allergy and Clinical Immunology: In Practice.¹

Jodi Shroba, APRN, MSN, CPNP, is the lead author and chair of the AAAAI FI Work Group. Her FI experience includes serving on the Children’s Mercy Hunger-Free Hospital Council and the medical advisory board of the Food Equality Initiative.

Food Insecurity Knowledge and Screening

In the fall of 2020, the work group surveyed a random sample of AAAAI members. COVID-19 fatigue may have played a part in the survey’s low response rate (6.3%), but it’s possible that lack of FI knowledge kept members from responding. If so, the survey may overestimate the FI knowledge base. Most respondents were allergists, female and white and worked in urban or suburban areas. The lack of diversity in the respondent sample may also skew results, especially because FI has had a greater impact on underrepresented communities.

The survey found 71.2% of respondents didn’t know if their FA patients experienced FI within the past six months. Only 24.5% routinely screened for FI. According to recent research, this suggests that fewer allergists screen for FI than do physician practices (30%) and hospitals (40%).² Sixty-six percent of respondents were aware of general food banks in their area, but only 5.7% knew of allergen-free pantries, and 28.3% reported not being aware of any available FI resources.

Barriers to Screening

The most common barrier to FI screening was lack of knowledge (70%), followed by not having resources to give food-insecure patients (40%). It is also possible that FI assumptions keep allergists from screening: 27.8% said they didn’t think FI was an issue for their patients, and 63.9% reported their patients have never discussed struggling to afford safe foods.

Sixty percent of respondents were interested in implementing FI screenings. They requested logistical support — FI conversation tips and validated screening questionnaires — and FI resources, like pantry lists, pamphlets and digital materials.

Guidance on Implementing Screening

Responding to this interest, the work group offered the following FI screening advice:

1. Prepare: Learn about FI. In addition to its own report, the group recommends the FI toolkit from the American Academy of Pediatrics (AAP).³
2. Select a screening tool and method: Annual, universal screening will decrease provider bias and stigma. The most validated clinical screening tool is the Hunger Vital Sign (see below).
3. Gather resources: Compile FI resources and highlight FA-sensitive ones. (See the full study for a starter list.) Federal FI programs include the Supplemental Nutrition Assistance Program (SNAP), the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), and the Emergency Food Assistance Program, but none have specific provisions for families with FA.
4. Get Involved: Create or join an FI group. For example, the Children’s Mercy Hunger-Free Hospital Council (HFHC) is a multidisciplinary team that works to improve the health care system’s response to FI, which is consistently identified as a priority issue in the hospital’s community health needs assessment. Initiatives supported by the HFHC include the Kids Eat Free summer food service program, fresh produce distribution and the community garden. Representation from the FA community lends a valuable perspective to the council, helping to ensure that programs to address FI are inclusive and equitable.

Future Areas of Study

More research is needed to understand the impact of FI on FA patients. Because FI has a greater impact on Latinx, Native American and Black communities, the work group would like to see increased diversity in FI and FA study samples. Future studies could include the impact of socioeconomic status on FA, whether specific FAs could be red flags for FI, and whether adding an FA question to the current Hunger Vital Sign tool would be helpful.

Learn more about food allergies and food insecurity

Jodi Shroba, MSN, APRN, CPNP
Food Allergy Program Coordinator, Allergy, Asthma and Immunology
jashroba@cmh.edu
(816) 960-8885

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

References:

1. Shroba J, Das R, Bilaver L, et al. Food insecurity in the food allergic population: a work group report of the AAAAI Adverse Reactions to Foods Committee. J Allergy Clin Immunol Pract. 2022;10(1):81-90. doi:10.1016/j.jaip.2021.10.058

2. Fraze TK, Brewster AL, Lewis VA, Beidler LB, Murray GF, Colla CH. Prevalence of screening for food insecurity, housing instability, utility needs, transportation needs, and interpersonal violence by US physician practices and hospitals. JAMA Netw Open. 2019;2(9):e1911514. Published 2019 Sep 4. doi:10.1001/jamanetworkopen.2019.11514

3. Screen and Intervene: A Toolkit for Pediatricians to Address Food Insecurity. Developed by the American Academy of Pediatrics (AAP) and the Food Research & Action Center (FRAC). January 2021.

In its 18^th consecutive year of funding from the National Institutes of Health (NIH), the Chronic Kidney Disease in Children (CKiD) study continues to provide groundbreaking and novel findings with an incredible impact on children with chronic kidney disease (CKD). Children’s Mercy Kansas City is one of two lead centers—and among more than 50 participating nephrology programs throughout North America—that follows children in the study  longitudinally and studies  a variety of outcomes associated with their CKD status.

Likewise, Children’s Mercy is a leader in the International Pediatric Peritoneal Dialysis Network (IPPN), SCOPE, NAPRTCS and other collaboratives advancing the understanding and treatment of pediatric kidney disease.

Bradley Warady, MD, Division Director of Pediatric Nephrology; Director, Dialysis and Kidney Transplantation and Professor of Pediatrics, University of Missouri-Kansas City School of Medicine, is Co-Principal Investigator of the CKiD and IPPN projects, and shares key clinical findings from seven collaborative research and quality initiatives involving the Children’s Mercy Pediatric Nephrology team and national/international colleagues in 2021.

1. The impact of blood pressure on CKD progression

A CKiD study analyzing longitudinal ambulatory blood pressure monitoring (ABPM) data from 679 children¹ confirmed that children who exhibited poor control of their mean arterial blood pressure also had more rapid progression of CKD, with a different pattern in those with glomerular versus non-glomerular disease. The importance of this study is that it addressed a modifiable risk factor for CKD progression. Whereas there are risk factors that cannot be altered, such as gender and genetics, blood pressure is a factor that can be controlled in most cases, and as this study revealed, can potentially exert a significant influence on the progression of CKD.

2. Socioeconomic factors disproportionately impact cardiovascular health in African American children with CKD

Another CKiD study demonstrated some cardiovascular risk factors, specifically high blood pressure and high left ventricular mass index, are influenced by socioeconomic status.² The study looked at data from more than 600 children, and the African American population was disproportionately affected by adverse socioeconomic factors such as maternal health, food insecurity, home income or insurance status. This study, which was featured as one of the best articles of the year by the American Journal of Kidney Diseases, demonstrated how social determinants of health can adversely affect both children and adults with CKD.

3. Development of a new estimating equation for kidney function

Clinicians use glomerular filtration rate (GFR) as a measure of kidney function, and over the years, there have been a variety of different equations—and a number of different variables—used to estimate it. By using data from 928 participants in CKiD, the study team published new estimating equations for individuals with CKD from age 1 through 25 years.³ The average of the creatinine and cystatin-based equations, without race coefficients, yield unbiased estimates of GFR. These updated equations are vital to closely and accurately monitor the progression of CKD in patients and are now being shared and adopted throughout the worldwide nephrology community.

4. 14 years of patient outcome data published, informing global care

This year, the IPPN published information regarding key factors that influence the morbidity and mortality of the global pediatric PD population.^4,5 In addition to reviewing important clinical management and outcome data collected over the course of the registry pertaining to nutritional status, anemia, CKD-MBD, preservation of residual kidney function and growth, it also highlighted the significant roles that infection and cardiovascular disease play in terms of patient survival. The international scope of the registry helped assess risk factors related to the geographic location of the patient and the economic status of various regions of the world and emphasized the importance of ongoing global advocacy and support to enhance the care of all children with end-stage kidney disease (ESKD) on maintenance dialysis. .  

5. Dialysis outcomes of children  with SLE

Limited information exists on the outcome of dialysis for children with lupus nephritis (LN) compared to children on dialysis with non-lupus glomerular disease.  In a retrospective NAPRTCS cohort study⁶, children with LN were found to have a higher risk of hospitalization and to be less likely to receive a kidney transplant in the first three years after dialysis initiation. Non-white race was also associated with a lower rate of kidney transplantation. The study calls attention to the need to address  risk factors for hospitalization of children with LN,  in addition to determining the actions  necessary to help achieve equitable access to transplantation.

6. Culture-negative peritonitis in children on PD

The identification of a causative organism in children with peritonitis helps optimize cure rates and avoid unnecessary antibiotic exposure. Unfortunately, culture-negative peritonitis is common. In a study conducted by the SCOPE collaborative⁷ based on 5.5 years of observation, 27% of peritonitis episodes were culture-negative. Most importantly, a survey of participating sites revealed marked variability of effluent sampling and culture techniques, a possible contributing factor to the high culture-negative rate. The findings point to an opportunity to improve standardization of PD effluent evaluation  using quality improvement methodology, as is now being carried out by SCOPE, and ideally improve organism detection.    

 7. Quality improvement initiatives can improve vein preservation over a child’s lifetime

Hospitalized children with CKD frequently have intravenous (IV) lines placed which can cause long term injury to their vasculature. For those children whose CKD worsens over time and who ultimately require the use of dialysis, damaged vasculature can hinder or prevent the development of an arteriovenous fistula (AVF) for the performance of hemodialysis, an important clinical burden during childhood and into adulthood.

An institutional quality improvement initiative and subsequent publication from Children’s Mercy featured a call to “Save the Vein.”⁸ It identified and implemented the steps necessary to prioritize IV-line placement in the dominant arm and preserve vasculature in the non-dominant arm. Whereas only 47 percent of children were having IVs placed in the preferred arm at baseline, by the end of this quality improvement project, it rose to 94 percent. The project demonstrated how dissemination of appropriate education and auditing of clinical practice can help improve the quality of care over a child’s lifetime.

Focusing on quality of life for kids with CKD

“The primary goal for these studies is to benefit and support children with CKD—to improve their outcomes and reduce their risk for additional burdens as they age,” says Dr. Warady. “Recognition of key risk factors for poorer outcomes, followed by prompt and successful targeted interventions, has the potential to lessen those risks and purposefully improve kids’ quantity and quality of life. Children’s Mercy will continue to work with colleagues in  CKiD, IPPN, SCOPE, NAPRTCS and other significant collaborative research efforts with a goal to continually improve the care, management and outcomes of children who have CKD and ESKD.”

References

1)  Dionne JM, Jiang S, Ng DK, Flynn JT, Mitsnefes MM, Furth SL, Warady BA, Samuels JA; CKiD study group. Mean Arterial Pressure and Chronic Kidney Disease Progression in the CKiD Cohort. Hypertension. 2021 Jul;78(1):65-73.

2)  Sgambat K, Roem J, Brady TM, Flynn JT, Mitsnefes M, Samuels JA, Warady BA, Furth SL, Moudgil A. Social Determinants of Cardiovascular Health in African American Children With CKD: An Analysis of the Chronic Kidney Disease in Children (CKiD) Study. American Journal of Kidney Diseases. 2021 Jul; 78(1):66-74.

3)  Pierce CB, Muñoz A, Ng DK, Warady BA, Furth SL, Schwartz GJ. Age- and sex-dependent clinical equations to estimate glomerular filtration rates in children and young adults with chronic kidney disease. Kidney International. 2021 Apr; 99(4):948-956.

4)  Borzych-Dużałka D, Schaefer F, Warady BA. Targeting optimal PD management in children: what have we learned from the IPPN registry? Pediatric Nephrology. 2021 May;36(5):1053-1063.

5)  Ploos van Amstel S, Noordzij M, Borzych-Duzalka D, Chesnaye NC, Xu H, Rees L, Ha IS, Antonio ZL, Hooman N, Wong W, Vondrak K, Yap YC, Patel H, Szczepanska M, Testa S, Galanti M, Kari JA, Samaille C, Bakkaloglu SA, Lai WM, Rojas LF, Diaz MS, Basu B, Neu A, Warady BA, Jager KJ, Schaefer F. Mortality in children treated with maintenance peritoneal dialysis: Findings from the International Pediatric Peritoneal Dialysis Network Registry. American Journal of Kidney Diseases. 2021 Sep;78(3): 380-390. 

6)  Wasik H, Chadha V, Galbiati S, Warady B, Atkinson M.  Dialysis Outcomes for Children with Lupus Nephritis Compared to Children with other Forms of Nephritis: A Retrospective Cohort Study. American Journal of Kidney Diseases. 2021 Aug; 28

7)  Davis K, Bryant K, Rodean J, Richardson T, Selvarangan R, Qin X, Neu A, Warady B.  Variability in Culture-Negative Peritonitis Rates in Pediatric Peritoneal Dialysis Programs in the United States. Clinical Journal of the American Society of Nephrology. 2021  Feb; (2): 233-240

8)   Singh NS, Grimes J, Gregg GK, Nau AE, Rivard DC, Fields M, Flaucher N, Sherman AK, Williams MU, Wiley KJ, Kerwin K, Warady BA. "Save the Vein" Initiative in Children With CKD: A Quality Improvement Study. American Journal of Kidney Diseases. 2021 Jul;78(1):96-102.

According to the Centers for Disease Control, new diabetes cases have decreased over the last decade, except in people under 20. In fact, in 2018, approximately 210,000 children and adolescents younger than age 20—or 25 per 10,000 U.S. youths—had been diagnosed with diabetes. This included 187,000 with type 1 diabetes.¹

The increasing frequency of both type 1 and type 2 diabetes in children and adolescents is a growing clinical and public health concern. Studies show long term that poor disease control at any age significantly raises the lifetime risk of serious complications, including heart and kidney disease, blindness and death.

Partners in Improving Pediatric Diabetes Care

In 2017, The Leona M. and Harry B. Helmsley Charitable Trust awarded funding to Children’s Mercy Kansas City to address these growing concerns by embarking on a grant project to achieve performance improvement in health care systems, leveraging predictive analytics technology developed by Cyft, Inc. The project’s goal was to use big data to identify high-risk youth with type 1 diabetes for more intensive intervention. The current grant extends the implementation of that work.

Mark Clements, MD, PhD, pediatric endocrinologist, Director of Endocrine/Diabetes Research, and Medical Director of the Pediatric Clinical Research Unit at Children’s Mercy Kansas City; and Leonard D’Avolio, Assistant Professor, Harvard University and Brigham and Women’s Hospital, and CEO, Cyft, Inc., are leading this project.

Also providing leadership to the current project are Sanjeev Mehta, MD, MPH, advisory committee chair, Joslin Diabetes Center; Susana Patton, PhD, CDE, director of intervention development, Nemours Children’s Health System; Ryan McDonough, DO, champion for clinical quality improvement; and several staff and faculty from the Children’s Mercy Diabetes Center and other departments across the hospital. Laurel Koester and Ben Stang from the Helmsley Charitable Trust serve as program officers who engage in ongoing conversations with the team on all aspects of the project.

Leveraging Technology to Rapidly Learn

Initially, the project used the large volume of data captured from routine care of youth with type 1 diabetes, such as the free text notes found throughout electronic health records (EHRs). By combining EHR data with multiple other data sources — such as diabetes self-management device data and patient-reported outcomes data — the researchers were able to develop robust predictive models for clinically important outcomes. They focused on two preventable outcomes: deteriorating blood glucose (A1c) control, and hospitalization for diabetic ketoacidosis. Having robust models to predict these two outcomes gave the researchers important targets for improvement.

From this foundation, Dr. Clements, Dr. D’Avolio and colleagues have now developed a nascent initiative called the Rising T1DE Alliance. The idea is to bring researchers and diabetes centers with similar goals together to learn how to scale innovations based on the immense amount of data generated during routine diabetes care, and to rapidly test innovative approaches to care that hold promise for improving outcomes for these youth.

Grant Supports Creation of the Rising T1DE Alliance and its Rapid Learning Approach

Based on the success of the initial project, Children’s Mercy recently received $9.75 million in funding from the Helmsley Charitable Trust to support the launch and scaling up of the Rising T1DE Alliance and its proactive, rapid approach over the next three years. The goals of this funding cycle — which will continue leveraging the predictive analytics technology developed by Cyft — are to 1) apply patient- and family-centered design to the development and implementation of novel behavioral, mHealth and care delivery interventions, 2) test multiple interventions for effectiveness in improving each predicted outcome, 3) predict new clinically relevant outcomes, 4) test new data types and sources for their ability to improve outcome predictions, 5) evaluate the cost-effectiveness of various approaches, and 6) disseminate findings.

Once novel interventions have been tested and validated, the team’s learnings can be shared via playbooks with other clinics. With this approach, other clinics will have access to the details necessary to implement an intervention and/or predict an outcome, thereby saving time and resources and leading to better decision-making.

Current interventions being tested include:

• Remote patient monitoring, which involves frequent sharing of diabetes data and frequent video or audio micro-visits via telehealth. The goal is to deliver timely and personalized interactions, facilitating just-in-time discussions regarding current disease control and self-management.
• Text messaging interventions to nudge behaviors and support communication between families and the health care team.
• Behavioral economic interventions that incentivize youth for positive behaviors that promote health. The researchers think this may be of interest for youth with diabetes who are predicted to have a rise in their A1c because it may help them better manage insulin at meals. This is a first-of-its-kind intervention.
• Just-in-time diabetes education based on the real-time changes in a young person’s glucose levels.
• A screening and referral program for social determinants of health.

Early Results Show Improved Outcomes

Children’s Mercy is already leveraging data science to predict outcomes and to apply quality improvement methods and implementation science to improve diabetes outcomes.

Dr. Clements has presented early results from this research at high-impact meetings, including the International Society for Pediatric and Adolescent Diabetes, and team member Emily DeWit has presented findings at the Advanced Technologies & Treatments for Diabetes conference. Upcoming data publications are also anticipated.

Highlights include:

• A validated model to predict 90-day rise in Hemoglobin A1c.
• A validated model to predict 180-day risk for hospitalization due to diabetic ketoacidosis.
• Early evidence of clinically significant risk reduction for rising HbA1c with remote patient monitoring.

Moving forward, the Rising T1DE Alliance will bring academic- and industry-based innovators together with other interested diabetes centers, benefiting patients and their families. The initiative will help researchers to better understand patient behaviors, to implement timely and appropriate interventions, to continuously monitor outcomes across large clinic populations, and to share successes that other health care professionals can implement with confidence. This, in turn, will drive better care for children and adolescents with type 1 diabetes, reducing the lifetime risk of serious complications and improving satisfaction with the overall model of diabetes care.

Learn more about Pediatric Endocrinology and Diabetes at Children’s Mercy

Mark A. Clements, MD, PhD, Rick and Cathy Baier Family Endowed Chair in Endocrinology; Director, Endocrine/Diabetes Clinical Research; Medical Director, Pediatric Clinical Research Unit

maclements@cmh.edu

(816) 960-8803

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

Reference:

1. National Diabetes Statistics Report 2020: https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Accessed 7/14/2020.

Approximately 2.5 million infants are born at less than 32 weeks’ gestation worldwide every year, with approximately 75,000 of them born in the U.S. Many of these preterm infants develop the severe form of lung disease bronchopulmonary dysplasia (BPD) and have poor lung function. The longer-term effects can range from prolonged oxygen therapy to increased morbidity after common lung infections.

Postnatal steroids are among the few medications shown in randomized trials to be beneficial in ameliorating BPD. But there is wide variability across the specialty of neonatology related to treating premature infants with a medication that requires practitioners to walk the fine line between safety and efficacy.

In fact, a policy statement issued by the American Academy of Pediatrics on the topic concluded, “Because available data are conflicting and inconclusive, clinicians must use their own clinical judgment to balance the adverse effects of BPD with the potential adverse effects of treatments for each individual patient. Very low birth weight infants who remain on mechanical ventilation after 1 to 2 weeks of age are at very high risk of developing BPD.”¹

To provide neonatologists with better guidance when treating these infants, researchers with the Division of Neonatology at Children’s Mercy Kansas City in the Center for Infant Pulmonary Disorders are examining several clinically important questions using a combination of internal and external funding. These questions include:

• When is the best time to treat these patients with postnatal corticosteroids?
• Which premature infants would benefit most from corticosteroids?
• How do we measure respiratory function in premature infants and determine if inhaled therapies and other therapies are working?

As an active member of the BPD Collaborative, an international consortium of 26 institutions, and the Children’s Hospital Neonatal Consortium (CHNC), the goal for these researchers collectively is to utilize sophisticated databases and testing to help answer these questions for neonatologists in the U.S. and across the globe, eventually establishing more definitive guidelines related to caring for this vulnerable patient population.

Evaluating the Timing of Postnatal Corticosteroid Treatment for BPD

In the Level IV NICU at Children’s Mercy Kansas City, there was a wide variability with regard to timing of steroid treatment among preterm infants with evolving BPD. Alain C. Cuna, MD, Neonatologist, Assistant Professor of Pediatrics, University of Missouri-Kansas City School of Medicine, noticed that some clinicians chose to treat infants who remained intubated on moderately high ventilator settings at around 2 to 3 weeks of life. Others opted to delay treatment until the baby’s lungs had more time to mature and additional efforts to wean them from mechanical ventilation had been ineffective.

To examine the association between timing of steroid treatment and outcomes in high-risk preterm infants with evolving BPD, Dr. Cuna and his colleagues conducted a retrospective cohort study of preterm infants treated with low-dose dexamethasone for BPD in the Children’s Mercy NICU.

Infants treated with dexamethasone at day of life (DOL) 14 to 28 (moderately late group) were compared to infants treated at DOL 29 to 42 (delayed group).

Fifty-five infants (25 with moderately late treatment; 30 with delayed treatment) were identified for this research. The mean age at treatment was 23 days in the moderately late group, and 35 days in the delayed group. At the time of treatment, infants treated moderately late were more likely to be on high-frequency ventilation (96% versus 47%, P < 0.0001) and had a higher fraction of inspired oxygen (71 ± 18% versus 56.2 ± 18.4%, P = 0.005) compared to infants treated later.

Despite being the sicker group, moderately late-treated infants (14 to 28 days) were discharged at an earlier corrected age compared to infants with delayed treatment (29 to 42 days). In the Children’s Mercy cohort, earlier treatment also was associated with fewer days on mechanical ventilation, and fewer days on supplemental oxygen, as well as less treatment with repeat or rescue steroids. There was also a trend toward more tracheostomy among delayed-treated infants.²

These findings led Dr. Cuna and his colleagues to conclude that among preterm infants, earlier treatment with steroids could potentially modify the disease trajectory and allow for the sicker cohort to have better outcomes compared to delayed treatment.

Validating the Children's Mercy Results Nationwide

With this first study being limited to a small cohort, Dr. Cuna and his colleagues sought to validate their results in a larger patient database. Working with the CHNC, they posed the same question regarding timing of corticosteroid treatment and outcomes, this time via a multicenter retrospective cohort study looking at data from January 2010 to December 2016 from the Children’s Hospitals Neonatal Database and Pediatric Health Information System database.

The study population included preterm infants <32 weeks’ gestation treated with systemic corticosteroids after 7 days of age and before 34 weeks’ postmenstrual age. Stepwise multivariable logistic regression was used to assess the association between timing of corticosteroid initiation and the development of Grade 2 or 3 BPD as defined by the 2019 Neonatal Research Network criteria.

Using this much larger database, Dr. Cuna and his colleagues identified 598 corticosteroid-treated infants (median gestational age 25 weeks, median birth weight 760 grams). Of these, 47% (280 of 598) were first treated at 8–21 days; 25% (148 of 598) were first treated at 22–35 days; 14% (86 of 598) were first treated at 36–49 days; and 14% (84 of 598) were first treated at >50 days. After adjusting for birth characteristics, admission characteristics, center and comorbidities, the infants first treated at 36-49 days (aOR 2.0, 95% CI 1.1–3.7) and >50 days (aOR 1.9, 95% CI 1.04–3.3) had higher independent odds of developing Grade 2 or 3 BPD when compared to infants treated at 8–21 days.

The results from this much larger database were recently published in Pediatric Pulmonology.³ The results mirrored the findings that Dr. Cuna identified in the initial retrospective study at Children’s Mercy. In short, later initiation of treatment among preterm infants with systemic corticosteroids was associated with a higher likelihood of developing Grade 2 or Grade 3 BPD when compared to earlier intervention.

Based on this data, neonatologists at Children’s Mercy implemented a quality improvement project titled, “Using quality improvement to implement consensus guidelines for postnatal steroid treatment of preterm infants with developing bronchopulmonary dysplasia.” The project goal was to achieve over 90% adherence to consensus guidelines on use of postnatal steroids (PNS) in preterm infants for BPD within six months.⁴

Dr. Cuna’s overall objective is for the data to better inform guidelines and best practices regarding the best time to administer corticosteroids to premature infants with BPD for optimal results at other NICUs.

Researchers Use R21 Grant to Study Steroid Treatment Response in Infants with BPD

Tamorah Lewis, MD, PhD, and William Truog, MD, both Children’s Mercy neonatologists, were awarded a two-year, $455,856 R21 grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development to assess the genomic and metabolomic markers that correlate with steroid response in a group of preterm infants who have evolving BPD.

Their project is called “Less Lumping, Smarter Splitting: Genomics and Metabolomics of Systemic Steroid Response in Bronchopulmonary Dysplasia.” Their work complements the research done by Dr. Cuna, helping to clarify the genomic and metabolomics biomarkers of clinical response as a mechanism to identify a group of infants with the most favorable risk/benefit ratio, thus moving the field of BPD treatment toward precision medicine.

By better understanding steroid response variability, the team hopes to move BPD therapy into the age of personalized therapeutics in this group of infants using pharmacogenomics and pharmacometabolomics. In fact, Drs. Lewis and Truog believe their research has the potential to shift the paradigm from largely unexamined 20th Century population-based dosing regimens, with little account for patient inter-individual variability, toward a precision medicine approach.

To do this, they are using contemporary tools (genomics, metabolomics) to identify infants with the greatest likelihood of therapeutic benefit with the naturally associated minimization of development of adverse events by preventing steroid exposure to infants unlikely to respond. This precision therapeutics approach addresses a large gap in current knowledge and may lead directly to improved pharmacotherapy for infants with BPD.

Children’s Mercy is serving as the principal investigator for this research. Other sites recruiting infants for this study are the Children’s Hospital of Philadelphia, Nationwide Children’s Hospital (Columbus, Ohio), Arkansas Children’s Hospital and Children’s Hospital of Los Angeles.

Accurately Measuring Pulmonary Function in Premature Infants with BPD

Another long-standing gap in the care of premature infants with BPD is the inability to accurately measure pulmonary function and response to treatment with bronchodilators.

Though there are several types of equipment and techniques that are FDA-approved for these purposes in adults and children, there are currently no lung function tests that are practically feasible, clinically meaningful and widely used in infants.

Winston Manimtim, MD, Neonatologist and Medical Director, Infant Tracheostomy and Home Ventilator Program, is supported by intramural funding from Children’s Mercy and is investigating the use of forced oscillation technique (FOT) to measure respiratory mechanics in premature infants with BPD.

FOT is a noninvasive method that employs small amplitude pressure oscillations superimposed on normal breathing and therefore has an advantage over conventional lung function techniques because it does not require the performance of respiratory maneuvers. To date, this technique is FDA-approved in adults and children but remains largely experimental in infants and newborns.

A new device aimed specifically at newborns and infants (0 to 2 years of age) called tremoflo N-100 (“Neo”) uses a facemask to measure lung function at the patient’s bedside in only a few minutes while the infant sleeps normally. It uses an adapted version of the airwave oscillometry (AOS) to calculate the impedance of the lungs and quantify airway obstruction.

Though this device has been used to evaluate respiratory mechanics in newborn and term infants, to Dr. Manimtim’s knowledge, it has not been used in premature infants who are recovering from initial respiratory distress syndrome (RDS) and are developing BPD.

The study design is a pilot prospective cohort of 20 Children’s Mercy patients who successfully complete testing over the next year. In those subjects who are already being treated with a bronchodilator as part of their BPD medical management, a post-bronchodilator FOT measurement will be done 30 to 60 minutes after treatment to compare any changes in pulmonary mechanics.

When the study is completed, Dr. Manimtim hypothesizes that FOT and this new technology may tell researchers if a medication is actually working and, if so, how well the infant is responding, further advancing the ability to individualize these therapies for maximum benefit.

Targeting the Right Baby with the Right Medication at the Right Dose and Right Time

These researchers are focusing their collective efforts on finding better ways to individualize treatment for preterm infants at the highest risk for developing BPD, prescribing the right medication at the right dose and at the right time in their development. The division is using multiple research modalities, including database studies, prospective cohort studies and new device studies to answer these important questions related to BPD therapeutics.

By doing so, they can better inform the risk/benefit ratio for corticosteroids, ensuring the infants who receive these treatments will benefit most.

Learn more about BPD research at Children’s Mercy

Alain C. Cuna, MD, Neonatologist

accuna@cmh.edu

(816) 234-3300

Tamorah Lewis, MD, PhD, Neonatologist

trlewis@cmh.edu

(816) 234-3300

Winston Manimtim, MD, Neonatologist; Medical Director, Infant Tracheostomy & Home Ventilator Program

wmmanimtim@cmh.edu

(816) 234-3300

William Truog, MD, Director, Center for Infant Pulmonary Disorders

wtruog@cmh.edu

(816) 234-3300

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

References:

Watterberg KL, American Academy of Pediatrics. Committee on Fetus and Newborn. Postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics, 2010;126(4):800-808.

Cuna A, Lewis T, Dai H, Nyp M, Truog WE. Timing of postnatal corticosteroid treatment for bronchopulmonary dysplasia and its effect on outcomes. Pediatric Pulmonology, 2019;54:165–170.

Cuna A, Lagatta JM, Savani RC, Vyas-Read S, Engle WA, Rose RS, DiGeronimo R, Logan JW. Association of time of first corticosteroid treatment with bronchopulmonary dysplasia in preterm infants. First published: 11 August 2021 https://doi.org/10.1002/ppul.25610.

Hansen TP, Oschman A, Pallotto EK, et al. Using quality improvement to implement consensus guidelines for postnatal steroid treatment of preterm infants with developing bronchopulmonary dysplasia. J Perinatol 41, 891–897 (2021). https://doi.org/10.1038/s41372-020-00862-1.

Polycystic ovarian syndrome (PCOS) is a prevalent endocrine condition that affects an estimated 6%-12% of women of reproductive age in the United States.¹ PCOS develops in genetically predisposed females where the severity of clinical expression is compounded by environmental, nutritional and lifestyle factors. The genetic predisposition mainly affects ovarian function, manifesting in a tendency toward ovulation dysregulation and hormonal imbalance, which favors androgen production.

Short- and long-term consequences of menstrual dysfunction and hormonal imbalance may include:

• Hirsutism and severe acne
• Depression and anxiety
• Insulin resistance/metabolic syndrome
• Sleep apnea
• Weight gain and type 2 diabetes
• Nonalcoholic fatty liver disease
• Heart disease
• Endometrial hyperplasia/cancer
• Anovulation/hypofertility

Early diagnosis and treatment of PCOS may benefit the adolescent cosmetically by reducing clinical manifestations of hyperandrogenism, as well as offer symptomatic relief of menstrual dysfunction. Most importantly, however, early diagnosis and management of PCOS may reduce the development of associated conditions and complications.

Addressing PCOS with a Multispecialty Program

The Children’s Mercy Kansas City Multispecialty Adolescent PCOS Program (MAPP) is led by Tania Burgert, MD, Pediatric Endocrinologist; Associate Professor of Pediatrics, University of Missouri-Kansas City School of Medicine. Dr. Burgert has long been involved with the diagnosis and treatment of PCOS and is a well-recognized leader in the field, serving on the board of directors of the Androgen Excess and PCOS Society and on the medical/scientific advisory board of the PCOS Challenge.

To address the constellation of symptoms adolescents aged 13-21 with PCOS face, Dr. Burgert established one of the few multispecialty programs in the nation at Children’s Mercy.

Unique to the program is the array of clinical specialists involved in several dimensions of each patient’s care. The clinic includes endocrinologists who focus on metabolic and endocrine concerns; adolescent medicine specialists who address gynecological health and mental health needs, such as anxiety and depression; and dietitians who provide nutritional counseling to help achieve lifestyle and weight goals.

Multispecialty care enables the team to take an individualized treatment approach focused on educating patients and their families regarding what PCOS is and empowering them to take an active role in managing the condition.

To streamline care, MAPP clinicians see the patient in a central location, bringing services to the exam room and ensuring a unified diagnostic approach. At the conclusion of the appointment, the clinicians explain the patient’s diagnosis and give them a cohesive treatment plan with follow-up recommendations, serving as a central point of contact for all their questions and care.

Advancing Clinical Research

The MAPP at Children’s Mercy is also committed to the advancement of clinical research.

Children’s Mercy is the primary recruitment site for a National Institutes of Health-funded study, Trajectory of Ovarian Morphology During the Adolescent Reproductive Transition. Marla Lujan, PhD, Cornell University, is the principal investigator for the grant. Dr. Burgert and Dr. Romina Barral are the MAPP collaborators for this research, and Heidi Vanden Brink, PhD, is the postdoctoral fellow involved in this study.

The study examines ovarian morphology using 2D and 3D transabdominal ultrasound longitudinally during the first two years post menarche in the general adolescent population alongside tracking menstrual cyclicity and changes in reproductive hormones during this developmental window. The main goal of this ongoing study is to establish ovarian morphology as an early, reliable biomarker for normal versus aberrant reproductive maturation and a potentially early indicator of PCOS in the years immediately following menarche.

PCOS Patient Database Yields Original Research

The Children’s Mercy MAPP also established a REDCap database of over 500 MAPP patients for retrospective research to further the understanding of PCOS during adolescence. Recently, MAPP team members presented some findings of their research at the November 2020 Androgen Excess and PCOS Society and the April 2021 Pediatric Endocrine Society meetings. These studies include:

• Androgen Excess and PCOS Society Poster Presentation: Intraindividual Testosterone Variability Challenges the Diagnostic Process in Adolescents with PCOS. This poster included 73 adolescents seen in the MAPP and diagnosed with PCOS. Data suggested that a normal total testosterone at initial evaluation may not reliably rule out biochemical hyperandrogenism in adolescents. Total and free testosterone exhibit significant intraindividual variation when repeated within three months. Because biochemical hyperandrogenism is a central diagnostic feature of PCOS, caution should be used when relying on a single measurement for the diagnosis of PCOS in adolescents. Further prospective research is needed to corroborate these findings and to elucidate the relevance of other factors that may account for intraindividual variation.
• Pediatric Endocrine Society Oral Research Presentation: Transgender Identity Among Adolescents with PCOS. This abstract looked at 169 adolescents from the MAPP and found a slight difference in the prevalence of transgender identity between PCOS and non-PCOS, though not statistically significant. Interestingly, patients with greater degrees of hirsutism were more likely to identify as transgender. This may have implications for treatment goals in those who desire a transmasculine appearance or fear increased identity conflict with return of menstrual cycles. The team’s findings suggest that screening for gender dysphoria should be considered in practice recommendations for comprehensive adolescent PCOS programs.
• Pediatric Endocrine Society Presidential Poster Presentation: HbA1c as a Surrogate for Dysglycemia in Polycystic Ovary Syndrome (PCOS). Dysglycemia and insulin resistance are comorbidities of PCOS and may contribute to its pathophysiology, and therefore are important to reliably screen. In this study, investigators evaluated the agreement between HbA1c, a common clinical biomarker of dysglycemia, and oral glucose tolerance testing (OGTT)-derived measures of dysglycemia. The team found that although HbA1c is more clinically attractive, not requiring fasting blood measurements nor a two-hour time commitment, the findings did not support the use of HbA1c as a surrogate for assessments of dysglycemia in an adolescent population with PCOS. Low sensitivity suggests continued use of OGTT-derived metrics for dysglycemia in adolescents with PCOS. Interestingly, the research team noted that BMI may influence the ability of HbA1c to predict dysglycemia. Research is ongoing to elucidate the relevance of HbA1c uniquely in lean versus overweight populations.

Collaborate with the Children's Mercy Multispecialty Adolescent PCOS Program

The MAPP continues to build its database of adolescents diagnosed with PCOS. If you are interested in collaborating with Children’s Mercy to build a stronger database to study this patient population, please reach out to:

Tania Burgert, MD, Pediatric Endocrinologist 

tsburgert@cmh.edu

(816) 960-8803

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

Reference:

1. Centers for Disease Control website. Accessed 6/1/2021: https://www.cdc.gov/diabetes/basics/pcos.html.

Bronchopulmonary dysplasia (BPD) remains the most common complication of premature birth.^1,2 Currently, the most accepted definition of BPD is the need for oxygen or respiratory support at 36 weeks’ postmenstrual age (PMA).

Patients with severe BPD often have severe complications, including pulmonary hypertension, poor growth, long-term pulmonary morbidity, and neurodevelopmental disability.³ The term BPD is often used interchangeably with chronic lung disease of prematurity, or CLD.

Establishing a Multidisciplinary CLD Team

There are a lack of published guidelines and national standards for treating infants with severe BPD/CLD. However, the Children’s Mercy Kansas City Neonatal Intensive Care Unit (NICU), an 84-bed Level IV regional neonatal referral center, saw the need to establish a dedicated multidisciplinary CLD team to care for these infants, and was one of the first in the nation to do so.

Launched in 2010, this team follows a standardized approach to the diagnosis and management of infants with BPD/CLD who do not respond to standard therapies.

Over the past decade, this team has grown to include dedicated neonatologists supported by pediatric pulmonology; cardiology; otolaryngology; a facilitator/coordinator; primary bedside NICU nurses; neonatal nurse practitioners; respiratory therapists; a tracheostomy coordinator; clinical pharmacology; dietary; social work; psychology; a parent advisor group; occupational, speech and language therapies; and members of the infant tracheostomy and home ventilator, pulmonary hypertension and palliative care teams. This group meets biweekly to discuss each case to determine acute and long-term management.

Patient Population Characteristics

To determine whether a multidisciplinary CLD team approach can improve outcomes for this complex infant population, the Children’s Mercy Multidisciplinary CLD team recently published its experience in the Journal of Perinatology.

A total of 267 patients hospitalized from 2008 to 2018 were identified for a retrospective analysis. Patients born from 2008 to 2009 with CLD served as a reference data point but not a comparison group prior to the establishment of the CLD Multidisciplinary team in 2010.

Characteristics of this patient population:

• 56% male; 44% female
• 62.2% Caucasian; 22.8% African American; 5.7% Hispanic; 0.7% Asian; 7.5% other
• 26 weeks median gestational age at birth; mean 28.5 weeks
• 0.85 kg median birth weight; mean birth weight 1.3 kg
• 44% primary respiratory conditions (non-BPD)
• 24% extremely preterm infants (born <28 weeks’ gestation) with severe BPD
• 14% genetic conditions
• 6% cardiac anomalies
• 4% neurologic conditions
• 8% other
• Over 75% of all patients in the cohort received diuretics, systemic and inhaled steroids, and bronchodilators. Pulmonary hypertension was diagnosed in 37.2% of the patient population; 39.7% were treated with inhaled nitric oxide, and <18% required PDE5 inhibitors.⁴

Can a Multidisciplinary CLD Team Improve Outcomes?

Since 2010, mortality has improved for infants with tracheostomy cared for by the dedicated Multidisciplinary CLD team at Children’s Mercy. Most patients were categorized as having primary pulmonary and airway conditions that evolved into what is broadly considered chronic lung disease of infancy (CLDI), while one-quarter of the cohort had the strict definition of severe BPD.

The overall survival rate reported for these infants was 88.8%, with 65% of them being ventilator-dependent through a tracheostomy at the time of NICU discharge. Tracheostomy was not associated with the odds of death prior to NICU discharge. In a cohort of infants with severe BPD/CLD, secondary pulmonary hypertension was strongly associated with the need for a tracheostomy, or death, or tracheostomy and death.

Though not addressed in this study, unique to Children’s Mercy is the continuum of care that extends beyond NICU discharge for these patients via the Infant Tracheostomy and Home Ventilator Program. This neonatology-driven program, led by Winston Manimtim, MD, Neonatologist and Medical Director, is the only one in the U.S. serving as a medical home for these patients in a multidisciplinary setting with other key subspecialists, including pulmonologists, gastroenterologists and otolaryngologists.

This team’s improved survival rates in preterm infants with tracheostomy have been highlighted in other recent studies.

Improving the Odds for Technology-Dependent Infants

A recent survey done by the Children’s Hospital Neonatal Consortium found that among 31 children’s hospital NICUs, 41% had a self-designated multidisciplinary BPD team (unpublished data), indicating that more and more NICUs are realizing the benefits of implementing a consistent, coordinated multidisciplinary approach to caring for these inpatients.

This paper includes resources, such as guidelines and quality improvement projects, to help other providers investigate and develop a multidisciplinary team approach to care for this complex infant population.

To access these supplementary materials, visit https://doi.org/10.1038/s41372-021-00974-2.

Learn more about the Children’s Mercy Multidisciplinary CLD Team

Winston Manimtim, MD, Neonatologist; Medical Director, Infant Tracheostomy and Home Ventilator Program

wmmanimtim@cmh.edu

(816) 302-3592

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

References:

Northway WH Jr., Rosan RC, Porter DY. Pulmonary disease following respiratory therapy of hyaline-membrane disease, Bronchopulmonary dysplasia. N Engl J Med. 1967;276:357–68.

Doyle LW, Anderson PJ. Long-term outcomes of bronchopulmonary dysplasia. Semin Fetal Neonatal Med. 2009;14:391–5.

Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics. 2005;116:1353–60.

Hansen TP, Noel-MacDonnell J, Kuckelman S, Norberg M, Truog W, Manimtim W. A multidisciplinary chronic lung disease team in a neonatal intensive care unit is associated with increased survival to discharge of infants with tracheostomy. Journal of Perinatology. https://doi.org/10.1038/s41372-021-00974-2.

The National Institutes of Health estimates that 10,000 to 15,000 babies born in the United States develop bronchopulmonary dysplasia (BPD) each year. The risk of developing BPD increases the earlier a baby is born and the lower the birth weight. Infants born weighing less than 2.2 pounds are at the greatest risk for BPD. The number of cases of BPD has been increasing, most likely because of modern advances in medicine, which have enabled doctors to keep more very low birth weight, premature babies alive than in the past.¹

Investigating Why Some Premature Babies Develop BPD

Not all premature babies develop BPD. But what makes some more susceptible to BPD than others? That’s what Venkatesh Sampath, MBBS, MRCPCH, Neonatologist and Medical Director of the Neonatal Diseases Research Program at Children’s Mercy Kansas City, wanted to know.

Dr. Sampath noted that mammalian lung development progresses sequentially, with formation of the tiny air exchange units, called alveoli, happening after birth. In preterm infants, exposure to noxious stimuli such as infection, mechanical ventilation and hyperoxia injures lung blood vessels, disrupting formation of alveoli and resulting in BPD. ^2,3,4,5

Studies of infants who die of severe BPD have revealed severe disruptions in lung vascular growth and alveolar development. Unfortunately, little is understood about the molecular mechanisms that regulate normal lung vascular growth, limiting understanding of defective vascularization in BPD.

Identifying a Key Vascular Gene Essential for Lung Vascular and Air Sac Development

Though lung development is a highly complex and regulated process, Dr. Sampath’s lab focuses on key lung vascular genes such as the delta-like 4 (DLL4) gene that are important for lung air sac development. While DLL4’s role in embryonic and retinal vascular development is known, this is one of the first studies where anyone has looked at this powerful gene and its role in lung development in both mice and humans. Based on earlier work, Dr. Sampath hypothesized that DLL4 is required during critical stages of lung development for formation of lung blood vessels and alveoli (air-exchange units).

Dr. Sampath and his fellow researchers, Sheng Xia, Heather Menden, et al., used human autopsy samples from babies who died from causes other than lung disease, to show that DLL4 is expressed in lung blood vessels and endothelial cells (EC) very early (before birth) in lung development. DLL4 expression during lung development was also confirmed in two different mouse strains using conventional methods and single-cell RNA sequencing.

Then, they used a mouse model specially bred for this research lacking one copy of the DLL4 gene. They found that the mice also expressed DLL4 early in lung development in the lung endothelial cells. Dr. Sampath’s research showed that when the mice were missing one copy of this gene, the lung’s alveolar sacs and blood vessels didn’t develop as they should, indicating how important DLL4 is to lung development.

His research showed that DLL4 serves as a major regulator of normal lung vasculature, triggering a series of actions that signal to the endothelial cells when and where to grow and form new blood vessels. The lack of DLL4 resulted in disordered lung vessel formation initially that finally resulted in fewer lung blood vessels.

Dr. Sampath also found that when DLL4 is deficient in EC, alveolar type 1 (AT1) cells, the cells that line all alveoli and facilitate gas exchange, were also reduced. This results in impaired lung growth and air sac development. In a final step, they also showed that lung EC obtained from the human developing lung also require DLL4 for normal blood vessel branching.

Study Demonstrates Role of DLL4 in Regulating Cell Growth of Endothelial and Aveolar Type 1 Cells

This is the first study to demonstrate that DLL4 regulates microvascular growth and arborization during distal lung ontogeny and DLL4 deficiency programs deviant angiogenesis, disrupting lung vascular patterning and alveolarization. These phenotypic changes occurred concurrently with altered expression signatures of lung endothelial cell fate specification and notch signaling, as well as impaired expression of AT1 lineage markers.⁶

Studies employing drug-dependent vascular endothelial growth factor (VEGF) signaling blockade or VEGF rescue in experimental models of developing lung injury demonstrated the importance of VEGF in lung development.^7,8,9 These studies postulated “the vascular hypothesis,” i.e., vascular injury in the developing lung programming defective alveolarization.⁹

Dr. Sampath’s results support “the vascular hypothesis” from a lung development perspective by indicating that DLL4, an endothelial gene, is required for distal lung morphogenesis. This research team also demonstrated that hyperoxia, a major risk factor for BPD in premature infants, inhibits DLL4 expression in the developing mouse lung and human lung endothelial cells, indicating a potential role for DLL4 in BPD.

Future Research Direction

Future studies will examine cross-talk between endothelial cell DLL4 and other cell types required for distal lung development, and the relevance of deviant DLL4 signaling to impaired vascular development in BPD affecting preterm infants. The relevance of DLL4 signaling in BPD will be investigated in preclinical models of BPD using human genetics and cadaveric samples of infants who died of BPD. The lab is also testing therapies in preclinical models of BPD that can rescue deficient DLL4 signaling and the BPD phenotype. Ultimately, Dr. Sampath and his colleagues may one day work on therapeutic targets that may increase the DLL4 gene, protecting premature infants against lung injury.

Learn more about BPD research at Children’s Mercy

Venkatesh Sampath, MBBS, MRCPCH, Medical Director of the Neonatal Diseases Research Program

vsampath@cmh.edu

(816) 234-3591

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

References:

1. National Organization for Rare Disorders (NORD) website: rarediseases.org/rare-diseases/bronchopulmonary-dysplasia-bpd/. Accessed March 22, 2021.

2. Jobe AH, Bancalari E. NICHD / NHLBI / ORD Workshop Summary - Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2001;163:1723–1729.

3. Morty RE. Recent advances in the pathogenesis of BPD. Semin Perinatol. 2018;42(7):404–412.

4. Menden HL, Xia S, Mabry SM, Navarro A, Nyp MF, Sampath V. Nicotinamide adenine dinucleotide phosphate oxidase 2 regulates LPS-induced inflammation and alveolar remodeling in the developing lung. Am J Respir Cell Mol Biol. 2016 Dec;55(6):767-778. doi: 10.1165/rcmb.2016-0006OC. PMID: 27438994; PMCID: PMC5248953.

5. Menden H, Xia S, Mabry SM, Noel-MacDonnell J, Rajasingh J, Ye SQ, Sampath V. Histone deacetylase 6 regulates endothelial MyD88-dependent canonical TLR signaling, lung inflammation, and alveolar remodeling in the developing lung. Am J Physiol Lung Cell Mol Physiol. 2019 Sep 1;317(3):L332-L346. doi: 10.1152/ajplung.00247.2018. Epub 2019 Jul 3. PMID: 31268348; PMCID: PMC6766719.

6. Xia S, Menden H, Townley N, Mabry SM, Johnston J, Nyp MF, Heruth DP, Korfhagen T, Sampath V. Delta-like 4 is required for pulmonary vascular arborization and alveolarization in the developing lung. JCI Insight. 2021;6(7):e134170. https://doi.org/10.1172/jci.insight.134170.

7. Thébaud B, Abman SH. Bronchopulmonary dysplasia: Where have all the vessels gone? Roles of angiogenic growth factors in chronic lung disease. Am J Respir Crit Care Med. 2007;175(10):978–985.

8. Le Cras TD, Markham NE, Tuder RM, Voelkel NF, Abman SH. Treatment of newborn rats with a VEGF receptor inhibitor causes pulmonary hypertension and abnormal lung structure. Am J Physiol - Lung Cell Mol Physiol. 2002;283(3 27-3):555–562.

9. Thébaud B et al. Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: Evidence that angiogenesis participates in alveolarization. Circulation. 2005;112(16):2477–2486.

Dr. Srivastava’s research has validated the importance of cyclooxygenase enzyme-2 (COX2), prostaglandin E₂ (PGE₂), and prostanoid receptor EP2 in the podocyte as a critical pathway that may play an important role in hyperfiltration-mediated injury.

To study this further, he was awarded a five-year R01 grant from the NIH to work on targeting prostanoid receptor EP2, one of the four PGE₂ receptors, to mitigate hyperfiltration-mediated kidney injury to delay the progression of chronic kidney disease in children born with CAKUT.

Recently, his research has shown that elevated SNGFR results in increased fluid flow shear stress and increased expression of prostanoid receptor EP2 during early-stage CKD in animal models. He has now shown that urinary PGE₂ excretion precedes overt microalbuminuria and is a biomarker for early hyperfiltration-induced injury in children born with a solitary functioning kidney. Supported by his NIH funding, Dr. Srivastava published this research in Prostaglandins & Other Lipid Mediators in February 2020.¹

A second study, Upregulated Proteoglycan-related Signaling Pathways in Fluid Flow Shear Stress-treated (FFSS) Podocytes, was published in the American Journal of Renal Physiology in August 2020. In this study, Dr. Srivastava and his colleagues showed the importance of podocyte glycocalyx in response to FFSS, which builds on his previous work establishing the importance of COX2-PGE₂-EP2 axis and Akt-GSK3β-β-catenin signaling downstream of prostanoid receptor EP2. This was based on cell and animal work on fluid flow shear stress.^2,3,4 These studies allow us to develop potential therapeutic strategies to mitigate hyperfiltration-mediated injury.

And finally, in the original research article published in Frontiers in Physiology called Unilateral Nephrectomy Stimulates ERK and Is Associated with Enhanced Na Transport, the authors discuss the relevance of FFSS in tubular cells, resulting in activation of ERK signaling.⁵

Researching Development of Nephrotic Syndrome

Although primary nephrotic syndrome is a relatively rare condition, according to the NephCure Kidney International Foundation, it is responsible for 20% of kidney failure in children, making it an important research target.

Dr. Srivastava is well known for his expertise in idiopathic nephrotic syndrome as part of his clinical practice, which intersects with his laboratory research. He is recognized as a nephrotic syndrome specialist by NephCure, and he has studied the role of innate immunity in podocytes to better understand the mechanisms behind the development of nephrotic syndrome.

Dr. Srivastava is involved in clinical trials related to idiopathic nephrotic syndrome and is part of the National Institutes of Health multicenter studies, NEPTUNE, CureGN and FONT; American Heart Association (ECHO-NEPTUNE); and industry investigations (Abatacept, ATLANTIS, Duplex and DUET) as the Children’s Mercy site principal investigator.

Many of these trials are investigating therapies for children with treatment-resistant nephrotic syndrome. Children’s Mercy also participates in the Pediatric Nephrology Research Consortium, which provides Dr. Srivastava an opportunity to collaborate with other pediatric nephrologists around the country to participate in collaborative research.

Committed to Transformational Research

The Division of Pediatric Nephrology at Children’s Mercy is one of the most academically productive departments in the country, publishing 63 peer-reviewed manuscripts in 2020. Children’s Mercy physician-scientists are committed to leading transformational research, from bench to bedside, to create a world of well-being for all children with pediatric kidney disease.

To learn more about our research or to collaborate with us, contact Bradley Warady, MD, Division Director, Children’s Mercy Nephrology, at bwarady@cmh.edu.

Learn More About Pediatric Kidney Disease Research at Children's Mercy

Tarak Srivastava, MD, Director, Nephrology Research Laboratory at Children’s Mercy

tsrivastava@cmh.edu

(816) 234-3010

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

References:

1. Srivastava T, Ju W, Milne GL, Rezaiekhaligh MH, Staggs VS, Alon US, Sharma R, Zhou J, El-Meanawy A, McCarthy ET, Savin VJ, Sharma M. Urinary prostaglandin E2 is a biomarker of early adaptive hyperfiltration in solitary functioning kidney. Prostaglandins & Other Lipid Mediat. 2020 Feb;146:106403.

2. Srivastava T, Joshi T, Jiang Y, Heruth DP, Rezaiekhaligh MH, Novak J, Staggs VS, Alon US, Garola RE, El-Meanawy A, McCarthy ET, Zhou J, Boinpelly VC, Sharma R, Savin VJ, Sharma M. Upregulated proteoglycan-related signaling pathways in fluid flow shear stress-treated podocytes. Am J Physiol Renal Physiol. 2020;319(2):F312-F322.

3. Srivastava T, Dai H, Heruth DP, Alon US, Garola RE, Zhou J, Duncan RS, El-Meanawy A, McCarthy ET, Sharma R, Johnson ML, Savin VJ, Sharma M. Mechanotransduction signaling in podocytes from fluid flow shear stress. Am J Physiol Renal Physiol. 2018 Jan 1;314(1):F22-F34.

4. Srivastava T, Alon US, Cudmore PA, Tarakji B, Kats A, Garola RE, Duncan RS, McCarthy ET, Sharma R, Johnson ML, Bonewald LF, El-Meanawy A, Savin VJ, Sharma M. Cyclooxygenase-2, prostaglandin E2 and prostanoid receptor EP2 in fluid flow shear stress mediated injury in solitary kidney. Am J Physiol Renal Physiol. 2014;307(12):F1323-33.

5. Repetti R, Majumder N, Carneiro De Oliveira K, Meth J, Yangchen T, Sharma M, Srivastava T, Rohatgi R. Unilateral nephrectomy stimulates ERK and is associated with enhanced Na transport. Frontiers in Physiology. Feb. 3, 2021. https://doi.org/10.3389/fphys.2021.583453.

In addition, there is pressure for pain medicine to shift away from reliance on opioids, ineffective procedures and surgeries toward comprehensive pain management that includes evidence-based nonpharmacologic options.¹

Utilizing Acupuncture to Treat Pediatric Headache and Migraine

Children’s Mercy Kansas City implemented an acupuncture clinic to treat pediatric headaches and migraines in October 2015. The program began with one medical acupuncturist, Jennifer Bickel, MD, FAAN, FAHS. Two additional medical acupuncturists, Jennifer Dilts, DO, FAAP, and Anna Esparham, MD, were added to the team to meet increasing demand for acupuncture services. All three were trained at the Helms Medical Institute.

In a retrospective chart review of 154 visits to the Headache Treatment Center from September through November 2018 of patients ages 7-18, average headache intensity scores (measured on an 11-point pain numeric rating scale) decreased after a variety of interventions.

Specifically, acupuncture provided by a board-certified medical acupuncturist at the Headache Treatment Center decreased headache intensity significantly, mean change = 2.07 + 1.90 (n=24), p<.05.²

Demand for Acupuncture in the Emergency Department 

Headache accounts for 1% to 4% of all visits to the pediatric emergency department, making headaches the ninth most common reason for all emergency department visits for patients under age 15.

In addition to variable efficacy of headache treatments received in the emergency department, there are other limitations associated with this setting that can make it suboptimal for the acute management of migraine. Such limitations include a lack of headache-trained or -informed providers, limited targeted interventions and comfort measures used for active headaches, a higher rate of treatment with opioids, and unnecessary imaging. Developing alternative viable models for early therapeutic intervention of headaches may be advantageous to improve management and limit disability.²

Expanding Acupuncture Treatment to the Emergency Department and Other Subspecialties

To address the growing demand for acupuncture in the Emergency Department and in other subspecialities, the medical acupuncturists within the Children’s Mercy Headache Treatment Clinic received a 2019 education grant from the American Academy of Pediatrics Section on Integrative Medicine.

As grant winners, the Children’s Mercy acupuncturists created an abbreviated basic acupuncture training curriculum that was implemented at the academic medical center. The 10-hour acupuncture course offered interested clinicians an accessible way to learn two basic acupuncture techniques: battlefield auricular acupuncture (BFA) and Four Gates.

Once learned, both techniques could be integrated into care at the bedside, making it possible for the patient to receive a clinical assessment and acupuncture treatment during the same emergency department visit from the same clinician.

Learning methods included an online module with videos and articles, two live workshops, and additional home practice.

Over a period of approximately 18 months, 38 pediatricians from nine pediatric subspecialties (22 emergency medicine providers, plus specialists in gastroenterology, hospital medicine, palliative care, hematology/oncology, rehabilitation, sleep medicine, developmental and behavioral pediatrics, and neurology) completed the course.

Participants completed pre- and post-tests measuring knowledge and attitudes, and a skills-based exam. Participants earned 10 American Board of Pediatrics Maintenance of Certification Part 2 points and 10 continuing medical education credits for completing the course.

Evaluation of Basic Acupuncture Curriculum

To determine the effectiveness of the acupuncture curriculum, the course instructors surveyed participants. Results included:

• Knowledge regarding acupuncture significantly increased following curriculum completion.
• The course significantly increased participants’ perceived efficacy of acupuncture for acute and chronic pain.
• All participants successfully completed a skills-based exam.
• All participants felt that the course would influence their current medical practice.
• All participants felt confident utilizing basic acupuncture.
• All participants felt that they would recommend the basic acupuncture curriculum to a colleague.

In a separate study on acupuncture from the Children’s Mercy Emergency Department, the researchers found most staff, parents and patients reported willingness to use acupuncture. In fact, patients (60%) and parents (73%) were willing to add 15 to 60 minutes to their Emergency Department length of stay to complete an acupuncture treatment.

AAP Section on Integrative Medicine Awards Acupuncture Research First Place Honor

As the AAP grant winners, the team was invited to present their research abstract at the AAP National Conference & Exhibition in October 2020 at the Section on Integrative Medicine’s joint session on pain with the Section on Pediatric Emergency Medicine.

The project received the best abstract award for the meeting and generated significant interest from other pediatric institutions interested in collaborating to develop and implement similar programs for their physicians and patients.

Collaborate With Children's Mercy to Bring the Basic Acupuncture Curriculum to Your Institution

Jennifer Bickel, MD, FAAN, FAHS, Medical Director, Center for Professional Well-Being, Division of Neurology, Chief Headache Section

jlbickel@cmh.edu

(816) 302-3331

Jennifer Dilts, DO, FAAP, Division of Neurology, Headache Section

jjdilts@cmh.edu

(816) 302-3328

Anna Esparham, MD, FAAP, Director of Headache Treatment Center, Division of Neurology

aeesparham@cmh.edu

(816) 302-3320

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

References:

1. Tick H, Nielsen A, Pelletier KR, Bonakdar R, Simmons S, Glick R, Ratner E, Lemmon RL, Wayne P, Zador V. Evidence-based Nonpharmacologic Strategies for Comprehensive Pain Care: The Consortium Pain Task Force White Paper.

2. Esparham A, Boorigie M, Ablatt S, Connelly M, Bickel J. Improving Acute Treatment of Pediatric Primary Headache Disorders With a Novel Headache Treatment Center: Retrospective Review of Preliminary Outcomes. Journal of Child Neurology. DOI: 10.1177/0883073820952997journals.sagepub.com/home/jcn.

Pediatric tracheostomy is increasing, with 40% of tracheostomies performed in children <1 year of age.¹ The significant increase in the rate of tracheostomy in infants is partly attributed to the increased survival of extremely preterm infants with severe BPD who require long-term ventilation for several years.^2,3

Significant variation in practice has led to conflicting opinions on indications, feasibility and long-term prognosis of infants <1 year old undergoing tracheostomy.^1,4 Decannulation time, mortality and neurodevelopmental outcomes vary significantly based on the indication for tracheostomy and underlying diagnosis.⁴

Home Ventilator Program Provides Unique Opportunity to Study Tracheostomy Population

The outcomes of infants with tracheostomy have not been well described in the literature. However, Children’s Mercy Kansas City developed the Infant Tracheostomy and Home Ventilator Program in 2005. This neonatology-led program, headed by Winston Manimtim, MD, Neonatologist and Medical Director, is the only program in the U.S. serving as a medical home for these patients in a multidisciplinary setting with other key subspecialists, including pulmonologists, gastroenterologists and otolaryngologists.

The program has collected the data necessary to systematically examine several key factors related to outcomes in this specific patient population, contributing important research to this field. Their most recent retrospective study on tracheostomy and decannulation included:

• 204 infants who met the inclusion criteria from 2005 through 2015 with tracheostomy at <1 year of age and follow-up in the Home Ventilator Clinic. No patients were excluded from the study.
• Primary indications for tracheostomy were abnormalities related to: upper airway (13.7%); lower airway (16.7%); combined airway and lungs (BPD) (40.2%); cardiac (7.3%); neurologic (6.9%); and others (15.2%).
• 93% of infants were G-tube dependent for their nutritional support at discharge; the proportion of infants who were able to feed orally (7%) had tracheostomy only and did not need assisted ventilation at discharge. No patients were discharged with nasogastric tube.
• Mean age at hospital discharge for all infants was 6.5 months and median age was 7 months.⁵

Highlights Document Age at Tracheostomy, Decannulation

The team’s goal was to describe the respiratory, growth and survival outcomes of these patients. Results were published in the high-impact medical journal Pediatric Research.

Highlights included:

• The mean age at tracheostomy was 4.5 months with a median age of 3 months.
• Median age of decannulation was 32 months.
• The time from tracheostomy placement to complete discontinuation of mechanical ventilation was 15.4 months; and from tracheostomy to decannulation was 33.8 months.
• Mortality rate was 21% and median age of death was 18 months.
• Preterm infants with acquired airway and lung disease (BPD) and born at <28 weeks’ gestation had a significantly higher survival rate compared to term infants with various tracheostomy indications.
• The z-scores for weight and weight for length improved from the time of discharge (mean chronological age 6.5 months) to first year and remained consistent through 3 years of age.⁵

Findings Offer Guidance for Counseling and Care

With 204 infants in this cohort, it was one of the largest studies of its kind, a significant strength of this research. These infants had regular and consistent outpatient follow-up care from a dedicated team throughout the first 3-4 years of age, thanks to the Children’s Mercy Infant Tracheostomy and Home Ventilator Program. This large number allows for more extensive statistical modeling that can help guide families and care providers on important prognostic factors, outcomes and follow-up care plans throughout the first few critical years of life.⁵

Specific to the Children’s Mercy cohort, the team found through regression analysis that the premature infants had a much higher rate of survival compared to term infants with tracheostomy, as well as a higher rate of decannulation. The authors postulated that the improved overall survival outcomes in these very high-risk infants are the result of providing a dedicated multidisciplinary approach that ensures timely, regular and consistent delivery of both primary and subspecialty care, along with optimizing nutritional support to enhance pro-growth state, incorporating developmental surveillance in every clinic visit, and addressing caregivers’ psychosocial issues.

The team’s goal is that these insights will assist other clinicians as they provide families with counseling based on this data, helping them manage expectations for tracheostomy and home ventilator support, and aiding them in making better informed decisions on behalf of this vulnerable population.

Learn more about the Children's Mercy Infant Tracheostomy and Home Ventilator Program

Winston Manimtim, MD, Neonatologist; Medical Director, Infant Tracheostomy Care and Home Ventilator Program

wmmanimtim@cmh.edu

(816) 302-3592

Gangaram Akangire, MD, Neonatologist

gakangire@cmh.edu

(816) 302-3592

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

References:

1. Muller RG, Mamidala MP, Smith SH, Smith A, Sheyn A. Incidence, Epidemiology, and Outcomes of Pediatric Tracheostomy in the United States from 2000 to 2012. Otolaryngol. Head Neck Surg. 160, 332–338 (2019).

2. Overman AE, et al. Tracheostomy for Infants Requiring Prolonged Mechanical Ventilation: 10 Years’ Experience. Pediatrics 131, e1491–e1496 (2013).

3. Ehrenkranz RA, et al. Validation of the National Institutes of Health Consensus Definition of Bronchopulmonary Dysplasia. Pediatrics 116, 1353–1360 (2005).

4. Salley J, Kou YF, Shah GB, Mitchell RB, Johnson RF. Survival Analysis and Decannulation Outcomes of Infants with Tracheotomies. Laryngoscope 130, 2319–2324 (2020).

5. Akangire G, Taylor JB, McAnany S, Noel-MacDonnell J, Lachica C, Sampath V, Manimtim W. Respiratory, Growth, and Survival Outcomes of Infants with Tracheostomy and Ventilator Dependence. Pediatr Res. 2020 Oct. 3:1-9. doi:10.1038/s41390-020-01183-x. Online ahead of print.

Precise cardiovascular anatomy is required for neonatal surgical planning. CT angiogram is commonly used to complement echocardiography. However, in small neonates, CT angiogram can be challenging due to a lack of power-injectable vascular access and rapid contrast transit, secondary to higher heart rates.

At the Ward Family Heart Center at Children’s Mercy Kansas City, Non-Invasive Advanced Cardiac Imaging and Echocardiography are utilizing MRI techniques that make it possible to obtain high-resolution images in small neonates, yet limit their exposure to ionizing radiation.

In these cases, a swaddling technique is used to calm the infant for the MRI exam, eliminating the need for sedating anesthesia. Utilizing a blood pool contrast agent for MR angiography that can be infused in a small peripheral intravenous line enables the acquisition of these images necessary for surgical planning. These techniques are used in neonates weighing down to 2 kilograms.

MR angiograms and additional functional imaging also have been used in clarifying critical details in lesions, like vascular rings, Tetralogy of Fallot with pulmonary atresia and atrioventricular septal defect in neonates. This demonstrates that these MRI techniques are diagnostic in neonates, thus reducing the risks of CT and anesthesia while complementing echocardiography.

Utilizing Point-of-Care Ultrasound for Cardiac Evaluation During COVID-19

The novel coronavirus SARS-CoV-2 is known to cause significant cardiac dysfunction, effusion, thromboembolism and coronary dilation. As the COVID-19 pandemic spread across the nation and these cardiac complications began to surface in the pediatric population, Non-Invasive Advanced Cardiac Imaging and Echocardiography at Children’s Mercy began searching for ways to safely and effectively detect these issues.

In addition to traditional ultrasound equipment, the team quickly pivoted to adopt a hand-held ultrasound probe that can be connected to an iPad. Because the unit is significantly smaller and more compact, cleaning and sanitizing it after each patient exam is much simpler. Plus, the technology can be readily utilized at the bedside with diagnostic image quality.

The team’s workflow was to perform the point-of-care exam, and if the scan revealed findings requiring more comprehensive evaluation, a follow-up detailed echocardiography exam was planned. For those patients with normal exams, the detailed echo was deferred.

Overall, point-of-care ultrasound has helped improve workflow and expedite care for pediatric patients admitted for COVID-19, while ensuring safety of patients and health care workers. Thanks to its portability and ease of use, the heart center imaging team is now training critical care specialists and neonatologists at Children’s Mercy in how to perform these ultrasound examinations at the bedside, putting access to this lifesaving testing at their fingertips.

Serving as the Echocardiography Core Lab for FDA Investigation of New Transcatheter Pulmonary Valves

Since 2012, the Non-Invasive Advanced Cardiac Imaging and Echocardiography Lab at Children’s Mercy has served as the Echocardiography Core Lab for FDA investigation of the safety and effectiveness of transcatheter pulmonary valves.

These valves are being developed by Edwards Lifesciences and include the SAPIEN 3 and Alterra transcatheter heart valves. The lab continues surveillance of patients who received the SAPIEN valve, which has been recently approved by FDA for clinical use.

In order to monitor valve safety and effectiveness over a five-year time frame, patients receive from five to nine different echo studies pre- and post-implant for each device under investigation.

The lab has performed more than 1,500 echo studies related to these valves since 2012, validating the team’s expertise in pediatric echocardiography while providing access to longitudinal follow-up data on hundreds of patients.

Developing New Apps for Advanced Imaging

Like many non-invasive pediatric cardiology programs, Children’s Mercy utilizes Lean methodology and meets all guidelines from the American College of Cardiology and the American Heart Association for advanced cardiac imaging. The program utilizes 3D printing capabilities for surgical planning; has a robust telemedicine platform that offers image transfer, archiving and expert interpretation of cardiac imaging studies; and provides 3D echocardiography and myocardial strain imaging surveillance for oncology patients post-treatment through the hospital’s Cardio-Oncology Clinic.

A program under development places the program on the leading edge of pediatric cardiology by using a novel online module-based curriculum to enhance pediatric cardiology fellowsʼ echo education. Four interactive modules, focused on principles and interpretation of a normal echo, were delivered to fellows. All fellows completed pre- and post-tests, validated by independent expert imagers and surveys. All of the fellows participated in the pilot study. Test scores improved after completing the modules, and most fellows maintained a higher score at four weeks, suggesting good knowledge retention.

Learn More About Advanced Imaging at Children’s Mercy

Sanket Shah, MD, MHS; Co-Director of Advanced Cardiac Imaging and Director of Echocardiography

ssshah@cmh.edu

Erin Opfer, DO; Co-Director of Advanced Cardiac Imaging

ekopfer@cmh.edu

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

Though sleep disorders are common in the pediatric population, infants represent an understudied minority. Little research has been published on the subject of sleep-disordered breathing (SDB) in this population, even though it can have a significant impact on health during the formative years of neurocognitive development.

To address this issue, Zarmina Ehsan, MD, Pediatric Sleep Medicine, Children’s Mercy Kansas City, joined forces with the data science team led by Mark Hoffman, PhD, Chief Research Information Officer with the Children’s Mercy Research Institute, home to one of the most progressive and dynamic pediatric research programs in the world.

They utilized big data to conduct the first large-scale study on SDB in infants. Dr. Ehsan identified the gaps in currently available literature as:

1. Limited understanding of the evolution of SDB during infancy and beyond.
2. Paucity of centers performing infant polysomnography (PSG) and, therefore, available literature generated based on information from select centers.
3. Management of infant obstructive sleep apnea (OSA) based on extrapolation of available literature from older children, potentially increasing the risk of providing inappropriate therapy to this understudied and underserved population with SDB.

These gaps also make this population an ideal focus of data science.

Database Highlights

Children’s Mercy utilizes the de-identified electronic health record Cerner Health Facts. The hospital also manages the Standardized Health and Research data Exchange (SHaRE), a group of Health Facts contributors who have agreed to collaborate and share de-identified patient data. By employing this big data methodology, the researchers determined the demographics, sleep diagnoses, comorbid medication conditions, healthcare utilization and economic outcomes for this patient database. Earl Glynn, a data scientist in Dr. Hoffman’s group, developed an innovative method to characterize comorbidities in this data resource.

Highlights included:

• In a cohort of 68.7 million unique patients, over a nine-year period, there were 9,773 infants and young children with a diagnosis of SDB (obstructive sleep apnea [OSA], nonobstructive sleep apnea, and “other” sleep apnea) who met inclusion criteria, encompassing 17,574 encounters, and a total of 27,290 diagnoses across 62 U.S. health systems, 172 facilities and three patient encounter types (inpatient, clinic and outpatient).
• Thirty-nine percent of patients were female; 39% were 1 year of age (6,429); 50% were 1-2 years of age; and 11% were 2 years of age.
• The most common comorbid diagnoses were micrognathia, congenital airway abnormalities, gastroesophageal reflux, chronic tonsillitis/adenoiditis and anomalies of the respiratory system.
• Payer mix was dominated by government-funded entities.

Big Data Yields Insight into Comorbidities

This is the first study to utilize big data in this understudied population and to demonstrate the utility of large-scale de-identified electronic health record data in sleep research in general.

Interestingly, this study confirmed what we see clinically: that sleep-disordered breathing in infants and young children is multifactorial and closely linked to comorbid medical conditions.

Additional insights that are not widely known include:

• Chronic tonsillitis and adenoiditis were prevalent in 21% of the OSA cohort, compared to 0.6% of the base population within this age group (prevalence ratio of 36%).
• Adenotonsillar hypertrophy is a well-known risk factor for OSA in older children, although few studies also report that it can be prevalent as early as infancy.
• About 2.9% of this cohort had a diagnosis of jaw abnormality, compared to 0.1% in the general population within this age group. This phenotype had the second largest prevalence ratio (27.9), but was not present in the nonobstructive sleep apnea or “other” sleep apnea cohorts, which is not unexpected as micrognathia is a known risk factor for OSA in infants, particularly in those with a cleft palate.
• Congenital anomalies of the respiratory system were prevalent in 11% of the OSA cohort, compared to 0.8% of the base population. Retrospective clinical research has shown that congenital soft tissue airway abnormalities or bone abnormalities involving the face also predispose to OSA.
• Laryngomalacia is one of the leading causes of stridor, upper airway obstruction, and therefore OSA, in infants. Other airway abnormalities such as subglottic stenosis or tracheomalacia are often present as well.
• Prevalence ratios for “dependence on respirator/ventilator” and “other diseases of the lung” also ranked high at 11% each.
• A diagnosis of otitis media was also prevalent within the cohort. There are a handful of studies suggesting a high prevalence of middle ear effusion and otitis media in infants with OSA (particularly those with Down syndrome).
• Chromosomal abnormalities consistently scored high on prevalence ratio in all three cohorts, with a higher prevalence than in the base population.
• The link between gastroesophageal reflux and OSA in infants has been reported in the literature; however, the evidence for this is weak. In all three cohorts, this research found a higher prevalence of gastroesophageal reflux compared to the base population, but prevalence ratios did not appear to be significant.

Conclusions:

Dr. Ehsan and her colleagues concluded large-scale aggregate, de-identified EHR data provide a rich and untapped resource to examine these conditions. The team is in the process of pursuing further research targeting infants and young children to better understand the long-term outcomes of SDB in this patient population.¹

Learn more about Pulmonary and Sleep Telemedicine Services at Children’s Mercy

Zarmina Ehsan, MD, Pediatric Pulmonology, Pediatric Sleep Medicine; Clinical Assistant Professor of Pediatrics, University of Missouri-Kansas City School of Medicine

zehsan@cmh.edu • (816) 234-3700

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

References:

1. Ehsan Z, Glynn EF, Hoffman MA, Ingram DG, Al-Shawwa B. Small Sleepers, Big Data: Leveraging Big Data to Explore Sleep-Disordered Breathing in Infants and Young Children. SLEEPJ, 2020, 1–13. doi: 10.1093/sleep/zsaa176.

To reduce the risk of complications related to hemodialysis, the Children’s Mercy Kansas City Division of Nephrology has implemented several strategies. The institution of standardized infection prevention practices has resulted in nearly 1,200 consecutive days without an outpatient central line associated blood stream infection (CLABSI) in a hemodialysis (HD) patient. Vascular preservation protocols also are improving the long-term venous access options for these and future patients.

Five Actions to Reduce Risk of Infection

The Standardizing Care to Improve Outcomes in Pediatric End Stage Kidney Disease (SCOPE) collaborative has previously reported a CLABSI rate of 0.8 infections/100 patient months.²

As participants in the SCOPE collaborative since its inception in 2011, the Children’s Mercy hemodialysis program has implemented the recommended care bundle practices to reduce the risk of CLABSIs in its patient population.

Through quality improvement and human factors work, meticulous adherence to five key protocols and procedures has resulted in more effective catheter care and a substantial decrease in the risk of infectious complications. These five actions are:

1. Video audits of clinical staff while performing self-hand hygiene and patient care to ensure consistency and promote accountability. Routine video surveillance has proven essential in helping staff identify best practices and opportunities for improvement in their individual care management techniques.
2. Implementation of a standardized protocol for catheter connection/disconnection and exit site care including scrubbing the outside of the disconnect cap in the same manner as the hub.
3. Reinforcement of patient restrictions regarding patient showers and other water exposures, and repeated education of patients and families regarding the risks of infection associated with showering.
4. Standard use of ClearGuard^TM Caps and StatLock^® stabilizers.
5. Patient, family and staff participation in frequent education activities, employing the “teach-back,” learning technique and emphasizing the need for consistent catheter care to prevent infection.

This multifaceted infection prevention approach has resulted in an unprecedented nearly 1,200-plus days without a CLABSI in hemodialysis patients at Children’s Mercy.

This accomplishment was recognized in September 2020 by the CDC’s Making Dialysis Safer Coalition and will be presented at the Annual Dialysis Conference in March 2021.

Documenting Infection Rates and Buttonhole Practices for Pediatric AVF Cannulation

One key aspect of the Children’s Mercy HD infection prevention strategy is greater use of arteriovenous fistulas (AVF) for dialysis access, and its successful use of the buttonhole cannulation technique. In 2019, the Children’s Mercy team published its experience with AVF buttonhole cannulation in the Nephrology Nursing Journal, reporting the performance of approximately 5,600 cannulations over 215.5 patient months with no infections of the AVF.³

Vital to the Children’s Mercy team’s success with this method has been the attention to infection prevention details, including the use of a select group of highly experienced cannulators to develop the buttonhole and remove scabs; a 30-second vigorous scrub with the disinfection agent chlorhexidine and a one-minute dry time before and after scab removal; and masking of everyone present during cannulation.

To further document the role of buttonhole access, the team recently led the first multicenter study in children comparing buttonhole versus rope-ladder cannulation techniques utilizing data from the SCOPE collaborative, the results of which have been submitted for publication. Whereas the data provides additional evidence of the safety of buttonhole cannulation in pediatric hemodialysis patients, the need for further study in children is emphasized.

Data generated from a survey performed in conjunction with the study revealed that the majority of centers successfully performing the buttonhole procedure were characterized by small patient/nurse ratios and the use of strict antiseptic protocols.⁴

Save the Vein Has Long-Term Implications for Hemodialysis Patients

Vein preservation in children with end-stage kidney disease (ESKD) is crucial because of the potential need for hemodialysis over a lifetime. To that end, Children’s Mercy instituted an initiative called Save the Vein to increase the frequency of peripheral intravenous line (PIV) placement in the dominant arm for hospitalized pediatric patients with advanced chronic kidney disease.

Each hospitalized patient is given a bright pink Save the Vein armband that highlights which arm (non-dominant) and associated vasculature should be preserved, and this information is documented in their electronic health record. In addition to staff education, patients and families also have been educated about the importance of vascular preservation so they can advocate for themselves or their child.

At baseline and prior to starting the initiative, 47% of PIVs were placed in the patient’s dominant arm, with only 25% of PIVs placed in the dominant arm for children < 5 years. Over the two years since the initiative was launched, 93% of all PIVs were placed in the dominant arm; and in children < 5 years, 94% of PIVs were placed in the dominant arm.

The team concluded that education regarding the importance of vein preservation, along with implementation of a standardized process, can help direct PIV placement and potentially preserve vasculature in pediatric patients with CKD.⁵

The results of this quality improvement project were recently published in the American Journal of Kidney Diseases.

Learn more about Hemodialysis at Children’s Mercy

Bradley Warady, MD, Division Director, Pediatric Nephrology; Director of Dialysis and Transplantation; McLaughlin Family Endowed Chair in Nephrology; Professor of Pediatrics, University of Missouri-Kansas City School of Medicine

bwarady@cmh.edu

(816) 302-3010

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466 3729.

References:

1. United States Renal Data System. 2019 USRDS Annual Data Report: Epidemiology of Kidney Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2019.

2. Marsenic O, et al. Prevention of Central Line Associated Blood Stream Infections in a Pediatric Dialysis Unit. Pediatric Nephrol 2020 Jan; 35(1): 135-143.

3. Moore T, Brightman S, Dodson D, Warady B. Arteriovenous Buttonhole Access Cannulation in Pediatric Patients on Hemodialysis. Nephrology Nursing Journal July-August 2019 Vol. 46, No. 4.

4. Morgans H, Gruhler De Souza H, Richardson T, Claes D, Dharnidharka V, Lee M, Mahesh S, Muff-Luett M, Swartz S, Neu A, Warady B, for the SCOPE Collaborative. A Comparison of the Buttonhole and Rope-Ladder AVF Cannulation Techniques Within the SCOPE Collaborative. Submitted for publication.

5. Singh N, Grimes J, Gregg GK, Nau AE, Rivard DC, Fields M, Flaucher N, Sherman AK, Williams MU, Wiley KJ, Kerwin K, Warady B. “Save the Vein” Initiative in Children with CKD: A Quality Improvement Study. American Journal of Kidney Diseases. 2021 Jan. doi.org/10.1053/j.ajkd.2020.11.016.

These injuries result in significant financial burdens, costing almost $30,000 per child² and up to a total of $181,443,000 in 2010 for those aged 0 to 19 years admitted to the hospital.³ Beyond financial burdens, particularly in the orthopedic population, firearm injuries have implications for risk of spinal cord and nerve injury, amputation, deep infection, non-union⁴ and growth arrest.

Research Focuses on Children Under Age 10 Years

Emily Boschert, BA, University of Missouri-Kansas City School of Medicine, year 6 medical student, and Richard M. Schwend, MD, FAOA, FAAP, Interim Chairman, Department of Orthopedic Surgery and Musculoskeletal Medicine, recently presented a study virtually at the Pediatric Orthopedic Society of North America meeting addressing the risk for adverse outcomes in pediatric firearm-related musculoskeletal injuries that may lead to poor quality of life due to chronic health burden.

For this report, the authors focused on a retrospective analysis of firearm-related musculoskeletal injuries treated at Children’s Mercy from 1995 to 2017. During that 22-year timeframe, 189 children were identified and evaluated in two cohorts: age < 10 years and age ≥ 10 years.

The study’s purpose was to investigate the 22-year epidemiology of pediatric firearm injuries at Children’s Mercy and determine if children under 10 years of age had more adverse life outcomes as a result of the injury.

Statistics Demonstrate Adverse Outcomes

Of the 189 injured children:

• 46 (24.3%) were under 10 years old, with a bimodal distribution (figure 1).
• 32 were females and 157 were males.
• Over 90% of both age groups were from the Kansas City metropolitan area.
• Of the injured children, 163 (86.2%) were injured as the result of an assault, typically during the teen years.

Adverse outcomes were seen in 52 children (27.5% of total group), with 23.1% of those 10 years or older having an adverse outcome; and 41.3% of those under age 10 years old.

A total of 11 (5.8%) had a spinal cord injury and 38 (20.1%) had a serious nerve injury. Other adverse outcomes included three late deaths, seven amputations, 17 with a growth disturbance and 44 with a long-term disability.

Utilizing Data to Implement Change

Pediatric survivors of firearm injuries often have an adverse outcome (27.5%), including growth disturbance, amputation, long-term disability, often from spinal cord or nerve injury, and even death. Although children ≥ 10 years in the Children’s Mercy study were more likely to be injured by a firearm, children < 10 years when injured are the most vulnerable for adverse outcomes and future disability.

Going forward, the study proposes that continuing efforts should be used to analyze this information across various locations, providing systematic data on gun ownership and storage. A prospective registry of injuries, with special attention to those < 10 years-old that evaluates epidemiological data with clear descriptions of injury circumstances, risk factors for adverse outcome, and long-term clinical outcomes would be highly useful for properly characterizing injuries, and the overall burden firearms injuries have on these young patients’ disability-adjusted life years (DALY).

Figure 1

Firearm injuries involving the musculoskeletal system in children treated at Children’s Mercy Kansas City 1995-2017. Bimodal age distribution, with peak ages at 3 years and 15 years. Younger children are more frequently victims of unintentional shooting when someone else is handling the firearm. In the teen years, the shooting is more likely to be the result of an intentional assault. There is also a marked sex difference for older children, with boys being much more likely to be injured. Adult victims over 17 years are typically cared for at adult facilities.

Learn more about Pediatric Orthopedic Surgery at Children’s Mercy

Richard M. Schwend, MD, FAOA, FAAP, Interim Chairman, Department of Orthopedic Surgery and Musculoskeletal Medicine; Pediatric Orthopedic Surgery Director, Orthopedic Research Program; Past Chair, American Academy of Pediatrics, Section on Orthopedics; Past President, Pediatric Orthopedic Society North America; Professor of Orthopedic Surgery and Pediatrics, University of Missouri-Kansas City School of Medicine; Clinical Professor of Orthopedic Surgery, University of Kansas School of Medicine

rmschwend@cmh.edu

(816) 234-3693

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466 3729.

References:

1. Centers for Disease Control and Prevention National Center for Injury Prevention and Control. Web-based Injury Statistics Query and Reporting System (WISQARS). 2005. Available at www.cdc.gov/injury/wisqars. Accessed July 19, 2018.

2. Dowd MD, Sege RD. Council on Injury, Violence, and Poison Prevention Executive Committee; American Academy of Pediatrics. Firearm-related Injuries Affecting the Pediatric Population. Pediatrics. 2012 Nov;130(5):e1416-23. doi: 10.1542/peds.2012-2481. Epub 2012 Oct 18. PubMed PMID: 23080412.

3. Carter CW, Sharkey MS, Fishman F. Firearm-related Musculoskeletal Injuries in Children and Adolescents. J Am Acad Orthop Surg. 2017 Mar;25(3):169-178. doi: 10.5435/JAAOS-D-15-00642. Review. PubMed PMID: 28134675.

4. Perkins C, Scannell B, Brighton B, Seymour R, Vanderhave K. Orthopaedic Firearm Injuries in Children and Adolescents: An Eight-year Experience at a Major Urban Trauma Center. Injury. 2016 Jan;47(1):173-7. doi: 10.1016/j.injury.2015.07.031. Epub 2015 Jul 29. PubMed PMID: 26365475.

5. Boschert E, Stubblefield C, Schwend RM, Reid KJ. Twenty-two Years of Pediatric Musculoskeletal Firearm Injuries: Adverse Outcomes for the Very Young. J Pediatr Orthop 2020 in Press.

According to the Scientific Registry of Transplant Recipients (SRTR), the number of pediatric kidney transplants performed annually in the U.S. has remained fairly consistent over the past few years, with programs performing approximately 750 transplants annually.¹ Most important is the achievement of long-term graft function for those children with end-stage kidney disease (ESKD) who are recipients of a transplanted kidney.

Children’s Mercy Kansas City is recognized as one of the top 10 nephrology programs in the nation by U.S. News & World Report, and the kidney transplant program has incorporated a number of innovative practices into their management plan that are designed to enhance patient outcomes.

The program’s personalized approach to meeting each patient’s unique needs — including repeated surveillance biopsies, epitope matching and pharmacokinetic assessment of immunosuppressive medication — has contributed to a 100% three-year patient and graft survival rate for the past six years.

RESEARCH FINDS SURVEILLANCE BIOPSY DETECTS SUBCLINICAL REJECTION

Rejection is responsible for just under 50% of graft loss in the pediatric kidney transplant population. It is well recognized that early identification and treatment of allograft injury may improve survival.

The Children’s Mercy Pediatric Kidney Transplant team, led by Bradley Warady, MD, Division Director, recently published the largest pediatric experience in North America on surveillance biopsies in kidney transplant recipients. As noted in their Pediatric Nephrology publication, the results of the investigation were derived from a practice that was initiated at Children’s Mercy more than a decade ago based on the team’s hypothesis that a protocol surveillance biopsy offers the earliest opportunity for targeted interventions to address potentially modifiable histologic changes in pediatric kidney transplant patients.²

A retrospective review was conducted of 215 kidney surveillance biopsies obtained from 2008 to 2016 in 97 pediatric kidney transplant recipients. Surveillance biopsies were obtained at 6, 12 and 24 months post-transplant as part of the program’s standard of care.

Potentially modifiable histologic findings were seen in 38.1% of all surveillance biopsies. Subclinical rejection was found with increasing frequency across all time points, with an estimated 49% increase in the odds of a subclinical rejection finding per additional six months post-transplantation (aOR 1.49, 95% CI 1.06–2.09, p = 0.022). Among follow-up biopsies in patients who underwent treatment for subclinical rejection, 50% had no subsequent subclinical rejection and 18.8% showed histologic improvement. The complication rate associated with the biopsies was minimal.

The team concluded that surveillance biopsies are safe and offer the opportunity to identify and treat modifiable histologic changes in the pediatric kidney transplant population up to two years after transplantation. Long-term follow-up of these patients will provide valuable data on the impact of this intervention on patient and graft outcome.

THE ROLE OF EPITOPE MATCHING IN TRANSPLANT GRAFT SURVIVAL

Traditional HLA-DR antigen matching historically has been an important criterion when deciding whether or not to accept a particular kidney for transplantation. An HLA-DR mismatch with the first kidney transplant can be associated with less favorable long-term patient outcomes.

To improve donor/recipient compatibility, Children’s Mercy, in collaboration with the Midwest Transplant Network, has implemented a paradigm shift in its pediatric kidney transplant program for donor selection, incorporating HLA class II epitope matching.

In a study published in Pediatric Transplantation, Children’s Mercy reported how this practice potentially lowers the risk of donor-specific antibody development, in addition to providing enhanced personalized guidance regarding exposure to immunosuppressive medications.³

Further, this data helps guide living-related donor matching, allowing for recommendations for the best match possible when multiple donors (e.g., both parents) are viable candidates.

REDUCING TOXICITY WITH THERAPEUTIC DRUG MONITORING

Though therapeutic drug monitoring is not routine for most pediatric transplant programs, it is at Children’s Mercy. Since July 2010, all pediatric kidney transplant recipients have undergone therapeutic drug monitoring as the standard of care for the anti-rejection drug mycophenolate mofetil.

The patient’s blood samples are collected during the same inpatient visit as when the surveillance biopsies are performed at 6, 12 and 24 months post-transplant. Results provide the transplant team with individualized data, helping them optimize therapy to improve graft and patient survival.

In fact, the team has concluded that a fixed dosing regimen for mycophenolate mofetil results in unpredictable systemic exposure, while individualized dosing based on therapeutic drug monitoring targets drug exposure, helping effectively balance the risks of rejection versus toxicity in pediatric kidney transplant patients. Publication of the Children’s Mercy experience is forthcoming.

PERSONALIZED MEDICINE IMPACTS PATIENT OUTCOMES

Children’s Mercy has been performing kidney transplants for more than 30 years with outcomes that exceed national averages. One- and three-year allograft survival rates are 100%. In fact, the program’s graft and patient survival rates have been 100% since 2014.

Another SRTR metric, which complements the graft survival rate, is the hazard ratio — the relative risk of a program losing an organ within three years as compared to other programs across the country. This year, the hazard ratio places Children’s Mercy as one of the top two programs in the country.

Dr. Warady and the transplant team believe the level of personalized medicine the Children’s Mercy program has implemented as the standard of care has impacted these results, providing insights into steps that other programs could take to achieve similar patient outcomes.

REFERENCES

1 Scientific Registry of Transplant Recipients. OPTN/SRTR 2018 Annual Data Report: Kidney. Website accessed 9/3/2020: https://srtr.transplant.hrsa.gov/annual_reports/2018/Kidney.aspx.

2 Odum JD, Kats A, VanSickle JS, et al. Characterizing the Frequency of Modifiable Histological Changes Observed on Surveillance Biopsies in Pediatric Kidney Allograft Recipients. Pediatr Nephrol (2020).https://doi.org/10.1007/s00467-020-04624-1.

3 Bryan CF, Chadha V, Warady BA. Donor Selection in Pediatric Kidney Transplantation Using DR and DQ Eplet Mismatching: A New Histocompatibility Paradigm. Pediatr Transplant, 20: 926–930. DOI:10.1111/petr.12762.

© Copyright 2020 The Children’s Mercy Hospital

You’ve just walked into the Level IV NICU at shift change when the bedside nurse asks you to examine an infant. The baby is 41 weeks’ gestation, 3 hours old, and appears to be having seizures while undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy.

The baby’s heart rate is 130 beats per minute; temperature 33.5 degrees Celsius; blood pressure 82/44, mean 60; and O2 saturation is 87-90%.

In addition, mom has just walked into the NICU and sees the baby seizing. She is frightened for her child, crying and upset. The team awaits your direction.

What critical actions would you take to stabilize the baby, and save his life? Would you recognize the seizure activity? Acknowledge and care for the mother? Call for pediatric neurology support?

These are just a few of the many questions you might face. Would you be prepared? Fortunately, this is a multidisciplinary simulation and an opportunity to practice what you’d do in just such a case.

Multidisciplinary Simulation: Preparing for the Unexpected

From deliveries in the cardiac catheterization lab to how to put a baby who has decompensated on ECMO, the Multidisciplinary Simulation Program at the Children’s Mercy Kansas City Level IV NICU develops and practices scenarios such as these routinely. The Children’s Mercy Simulation Program supports the Neonatology Simulation team by providing high-fidelity mannequins in a learning lab that allows participants to film and de-brief each scenario. The program also has mobile mannequins and technology to provide on-site simulations in the NICU, and at facilities throughout the Kansas City area, as well as outreach hospitals.

Led by Jessica Brunkhorst, MD, Division of Neonatology Simulation Director, and Danielle Reed, MD, Associate Program Director, the Children’s Mercy program is more than a decade old and is one of the most comprehensive in the nation.

The Level IV NICU, Fetal Health Center and ECMO teams receive real-life training using high-fidelity simulators and a variety of complex scenarios several times a month. The NICU teams practice a different scenario each time, on-site, on demand, 24/7.

Simulations for the ECMO nursing specialists and physicians take place during 16 four-hour sessions each year (two full days quarterly) and are performed in collaboration with the NICU and PICU, focusing on low-volume, high-acuity cases. Prior to COVID-19, these sessions occurred in the simulation lab and were recorded for review and learning. They are now being conducted virtually. Participation is critical to credentialing for physicians and ECMO nursing specialists, and expands the team’s knowledge in preparation for real-life events.

The simulation program also conducts a skills lab for fellows six times a year, and performs a two-hour neonatal resuscitation refresher monthly for new residents at Truman Medical Center.

Each simulation includes a debriefing, and is followed by an evaluation used to further refine scenarios and teaching methods. Feedback often focuses on the need for better communication among team members in high-stress situations, and developing critical thinking skills.

Tapping the Children’s Mercy Expertise in Simulation

One of the many features that makes the Children’s Mercy program unique is the broad range of simulations the team has created. From delivery scenarios to mock codes, each case helps team members practice and refine different skill sets.

So, when the Organization of Neonatal-Perinatal Medicine Training Program Directors (ONTPD), a section of the American Academy of Pediatrics, decided to create a library of simulation cases available to programs nationally, they sought the expertise of the Children’s Mercy team.

Dr. Brunkhorst, Dr. Reed and their colleague, Jotishna Sharma, MD, MEd, DCH, Neonatologist, all contributed to the endeavor by serving on the editorial team for this national resource. Cases are available for review or download to individuals with an AAP account at aap.org.

The simulation program also participated in a multisite study for fellows in collaboration with Rainbow Babies & Children’s Hospital. This study utilized a modified training curriculum employing former NICU parents instead of standardized patients for each scenario, providing the fellows with hands-on experience handling delicate situations with families who actually had children in the NICU.¹

Bringing High-Fidelity Simulation to Community Hospitals

With a 150-county service area, Children’s Mercy receives referrals of the most critically ill and complex newborns from hospitals throughout the region.

Under Dr. Brunkhorst’s leadership, the Children’s Mercy Simulation Program is now working with some of these regional and community hospitals interested in high-fidelity simulation. Training is tailored to each hospital’s individual needs, focusing on improving the care of neonates in the community.

To date, the program has conducted simulations at 12 hospitals in the region. Plans are to continue to grow the program, making it available to even more hospitals in the near future.

Learn More About Multidisciplinary Simulation at Children’s Mercy

Jessica Brunkhorst, MD, Neonatal Division Simulation Director

jbrunkhorst@cmh.edu

(816) 302-8113

Danielle Reed, MD, Associate Program Director, Pediatric Residency Program

djreed@cmh.edu

(816) 460-1086

transformpeds.childrensmercy.org

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466 3729.

References

1. Families as Educators: A Family-centered Approach to Teaching Communication Skills to Neonatology Fellows. Parham D, Reed D, Olicker A, Parrill F, Sharma J, Brunkhorst J, Noel-MacDonnell J, Voos K. Journal of Perinatology (2019) 39:1392–1398. https://doi.org/10.1038/s41372-019-0441-7.

Most PPIs are extensively metabolized into inactive metabolites primarily by the hepatic cytochrome P450 2C19 (CYP2C19) enzyme. CYP2C19 genotypes have been linked to variability in PPI exposure and treatment response, with lower exposure associated with treatment failure and higher exposure associated with improved treatment efficacy.¹

Representing the Needs of Pediatric Patients

Recently, Valentina Shakhnovich, MD, Physician-Scientist with the Division of Pediatric Gastroenterology, Hepatology and Nutrition and Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation at Children’s Mercy Kansas City, served as a co-author on the international guidelines for dosing PPIs published in August 2020 by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The organization’s goal is to bring precision therapeutics to the patient’s bedside.

Dr. Shakhnovich, who has conducted novel research aimed at understanding the sources of variability in PPI treatment response in children, was the only pediatric gastroenterologist invited to contribute to the guidelines, which were developed based on expert opinion from pharmacogenetics leaders in the field.

Therapy Targeted to the CYP2C19 Gene

PPIs have been among the most commonly prescribed medications in adults and children, due in part to the perception that they have a high safety-to-risk profile. However, a large body of evidence is emerging that links adverse events with long-term PPI use.² Adverse events have included electrolyte imbalances (e.g., hypomagnesemia), infections, kidney disease and bone fractures.

Clinical CYP2C19 genotype testing results can provide clinicians with information to facilitate appropriate dose selection of PPIs. Essentially, the guidelines created dosing recommendations for first-generation PPIs, including omneprazole, lansoprazole, pantoprazole and dexlansoprazole. Based on genetic testing, patients can be divided into seven phenotype categories, ranging from ultra-rapid metabolizers to poor metabolizers. The guidelines recommend increasing the standard starting daily dose for ultra-rapid metabolizers, as well as for normal and rapid metabolizers when treating specific disorders like erosive esophagitis and H. pylori gastritis, while reducing the standard starting dose for those who are intermediate and poor metabolizers, especially if considering long-term PPI therapy.

Pediatric Recommendations

The CYP2C19-guided PPI dosing recommendations also apply to pediatric patients. PPI use in children is common and continues to increase. PPIs have U.S. Food and Drug Administration-approved indications in children for the short-term treatment of symptomatic GERD, healing of erosive esophagitis, treatment of peptic ulcer disease, and eradication of H. pylori. They are also considered the standard of care for pediatric eosinophilic esophagitis. However, off-label and potentially inappropriate use of long-term PPI therapy in children is also common, particularly in infants less than 1 year of age for uncomplicated, physiologic, gastroesophageal reflux and colic.

For children older than 1 year, there is emerging evidence that CYP2C19 genetic variation influences PPI pharmacokinetics and treatment response. A recent pilot study of CYP2C19 genotype-guided dosing of PPIs in children has been promising, and additional studies are ongoing. These investigations support genotype-based optimization of PPI therapy for children. However, very low clearance in preterm infants and infants less than 2-3 months old makes recommendations in the neonatal population more challenging to support.

Utilizing Noninvasive Breath Test Technology to Identify CYP2C19 Phenotype

Dr. Shakhnovich is conducting clinical research investigating the use of noninvasive breath test technology to identify children who would benefit from PPI dose adjustment based on the new CPIC treatment guidelines. The team involved in this line of research is assessing the utility of the 13C-pantoprazole breath test, which only requires the patient to breathe into a bag in lieu of a blood draw for genetic testing, with promising results.

Dr. Shakhnovich and her collaborators at the University of Missouri-Kansas City, University of Kansas Medical Center, The Center for Children’s Healthy Lifestyles and Nutrition, and Texas Christian University will present their findings in March 2021 at the American Society for Clinical Pharmacology and Therapeutics virtual meeting. A sneak peek at the data suggests that this test could offer a clinically useful, noninvasive method to identify children who would benefit from PPI dose escalation or dose reduction in as little as 60 minutes, without the need for a blood draw.

Long-term Benefits of PPI Guidance in the Pediatric Population

The benefit of using CYP2C19 genotype information to guide PPI therapy is that patients with phenotypes predictive of lower plasma drug concentrations from a given PPI dose can be identified upfront, and prescribed an increased starting dose of medication to increase the likelihood of PPI efficacy.

Conversely, for patients on chronic PPI therapy with phenotypes predictive of slower drug clearance and therefore higher systemic exposure to PPIs over time, clinicians may want to consider a dose reduction to minimize the risk of toxicity associated with long-term PPI use (overexposure).

These recommendations provide essential guidance, especially for pediatric patients who may begin PPI treatment at an early age and who may potentially be exposed to these medications over a much longer period of time than adults.

Learn more about Pediatric Gastroenterology at Children’s Mercy

Valentina Shakhnovich, MD, Pediatric Gastroenterologist and Clinical Pharmacologist; Associate Professor of Pediatrics, University of Missouri-Kansas City School of Medicine

vshakhnovich@cmh.edu

(816) 302-3068

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

References

1. Lima JJ, Thomas CD, Barbarino J, Desta Z, Van Driest SL, El Rouby N, Johnson JA, Cavallari LH, Shakhnovich V, Thacker DL, Scott SA, Schwab M, Uppugunduri CR, Formea CM, Franciosi JP, Sangkuhl K, Gaedigk A, Klein TE, Gammal RS, Furuta T. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19 and Proton Pump Inhibitor Dosing. https://cpicpgx.org/guidelines/cpic-guideline-for-proton-pump-inhibitors-and-cyp2c19/.

2. Jaynes M, Kumar AB. The Risks of Long-term Use of Proton Pump Inhibitors: A Critical Review. Ther. Adv. Drug. Saf. 10, 2042098618809927 (2018) https://doi.org/10.1177/2042098618809927.

One out of every 30 people suffers from a rare disease thought to be due to a mutation in their DNA. These mutations are present at birth or may be apparent early in life. In the past decade, genome-wide sequencing technologies have allowed an unprecedented increase in the discovery of mutations causing these diseases. However, because “blind spots” exist in current diagnostic sequencing technologies, only one-third of kids with rare diseases receive a genetic diagnosis from even the most advanced clinical molecular testing, meaning the majority of families are still waiting for a specific genetic cause of their child’s illness.¹

The Genomic Medicine Center at Children’s Mercy Kansas City wants to change that. Established in 2011, the center was the first of its kind with a pediatric focus. Today, under the direction of Tomi Pastinen, MD, PhD, the center is utilizing advanced sequencing technologies to detect these “blind spots,” contributing to better understanding of how mutated DNA in unexplored parts of the human genome, including regions regulating gene expression, can cause rare diseases. This work has helped to establish Children’s Mercy as the hub for pediatric molecular diagnosis.

Children’s Mercy has taken the unprecedented step of developing the world’s first outward-facing, cloud-based platform, providing live, interactive access to a database focused on solving pediatric rare diseases.

Genomic Answers for Kids Launches a New Paradigm in Rare Disease Research

Genomic Answers for Kids is a flagship initiative of the Children’s Mercy Research Institute and the Genomic Medicine Center. This research program is building a first-of-its-kind pediatric data repository to facilitate the search for answers and novel treatments. This program will collect and store genomic information and biological samples from children and their biological family members who are searching for diagnoses and are suspected to have rare genetic conditions. The program’s goal is to collect genomic data and health information of 30,000 children and their families over the next seven years, creating a database of nearly 100,000 genomes.

Though conventional practice in rare disease research is to take an exclusive, proprietary approach, Genomic Answers for Kids is establishing a new paradigm in this field. How is it doing this?

First, rather than focusing on a single medical mystery, the research initiative is including all children with a rare disease, who will represent the full spectrum of rare diseases, and their families. This makes it possible to help a great many patients on a global level.

Second, Genomic Answers for Kids is systematically employing an advanced set of genomic tools to uncover a greater number of inherited mutations in these patients. These tools include novel technologies, such as third-generation DNA sequencing and single-cell genomics. These technologies allow researchers to look at the “blind spots” in current diagnostic sequencing technologies by generating much longer DNA sequencing reads than conventional technologies have allowed, and to observe changes in the genome function. These techniques allow us to read the unexplored genomic space, which holds some of the answers the Children’s Mercy researchers and families are looking for.

Third, the program is openly sharing data with the wider international rare disease research community. This will lead to the fast-forwarding of the discovery of unconventional genetic variants, and will engage the stakeholders in the exploration and mitigation of the real barriers for genomic data sharing to advance rare disease diagnoses.

Pioneering a New Data Sharing Model

Genomic Answers for Kids is the only privately funded initiative at a nonprofit pediatric hospital that is genetically sequencing the DNA of patients and families with rare diseases, and sharing this de-identified genetic data with other investigators.

To further advance this discovery, Children’s Mercy has taken the unprecedented step of developing the world’s first outward-facing, cloud-based platform, providing live, interactive access to a database focused on solving pediatric rare diseases. Clinician-scientists across the globe can apply for access to this resource and compare the genomic makeup of their patients against individual cases that have already been sequenced, to help discover more relevant diagnoses.

Children’s Mercy also is uploading and sharing this sequencing information to the National Institutes of Health’s database of Genotypes and Phenotypes (NIH/dbGaP).

Genomic Answers for Kids Project Progress as of October 2020:

• 1,904 families enrolled

• 4,400 individuals enrolled

• 1,500+ families undergoing DNA sequencing analysis

• 863 families with initial results

• 180 new diagnoses

• 462,028 gigabases sequenced*

*Our genetic material, or DNA, is made up of a string of bases. When we sequence DNA, we read these bases. Each gigabase of DNA sequenced represents 1 billion bases read.

Collaborate with us to Find Answers

Genomic Answers for Kids began at Children’s Mercy in 2019 when the program reached out to nearly 20 different specialty divisions across the hospital, asking physicians to nominate patients who had not received a diagnosis via traditional molecular testing.

Now Children’s Mercy is reaching beyond its walls, collaborating with other academic medical centers to create an international network of institutions interested in accessing the rare disease resources available through Genomic Answers for Kids.

This collaborative model and innovative database is establishing an unprecedented paradigm in rare disease research, accelerating the pace of discovery for families seeking answers, and advancing the field of genomic medicine.

If your team is interested in collaborating with Genomic Answers for Kids at Children’s Mercy, please contact us at (816) 915-4200; or by email at GA4K@cmh.edu; or visit childrensmercy.org/genomicanswers, where you can nominate patients once engaged.

Learn more about Genomic Answers for Kids at Children’s Mercy

Tomi Pastinen, MD, PhD, Director, Genomic Medicine Center; Lead Study Investigator, Genomic Answers for Kids

tpastinen@cmh.edu • (816) 915-4200

transformpeds.childrensmercy.org

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

References

1. Clinical Genome Sequencing in an Unbiased Pediatric Cohort. Thiffault I, Farrow E, Zellmer L, Berrios C, Miller N, Gibson M, Caylor R, Jenkins J, Faller D, Soden S, Saunders C. Genet Med. 2019 Feb;21(2):303-310. doi: 10.1038/s41436-018-0075-8. Epub 2018 Jul 16.PMID: 30008475.

The relationship between the brain and the gut has been long recognized, but the subspecialty of neurogastroenterology is a relatively new one, especially in the world of pediatrics.

While serving as Chair of Neurogastroenterology and Motility for the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, or NASPGHAN, Jose Cocjin, MD, Chief, Section of Neurogastroenterology and Motility, Children’s Mercy Kansas City, proposed a symposium focused on this emerging topic.

The result was a full-day symposium presented at the 2018 NASPGHAN meeting entitled Advances in Motility and Neurogastroenterology — AIMING (Advances in Motility & in Neurogastroenterology) for the Future.

Exploring Pediatric Neurogastroenterology

This symposium brought together more than 35 leading experts from throughout North America to review the state-of-the-art advances in the diagnosis and management of motility and functional disorders in children. More than 350 attended the event. Representing Children’s Mercy were Dr. Cocjin and his colleague, John Rosen, MD, pediatric gastroenterologist. The NASPGHAN symposium explored clinical paradigms in pediatric gastrointestinal motility disorders and provided a foundation for advancing new scientific and therapeutic research strategies. Presentations were divided into esophageal, antral duodenal and colorectal modules. Breakout sessions focused on scientific insights into the diagnosis and management of pediatric functional gastrointestinal and motility disorders in a systematic, segment-based approach.

Publishing Symposium Proceedings

The result of the 2018 symposium was the online publication of the proceedings in the Journal of Pediatric Gastroenterology and Nutrition in May 2020.¹

Topics addressed in the proceedings included:

• The Pediatric Esophagus: The Diagnosis and Management of Dysphagia, Pain, Cough and Beyond

• Gastric and Small Intestinal Sensory and Motor Dysfunction

• Advances in Evaluation and Management of Anorectal and Colonic Dysfunction

The proceedings included insights into sophisticated technology developed to measure the motor and sensory characteristics of the upper and lower GI tract, leading to improved understanding of the pathophysiology of most childhood neurogastroenterological disorders. The current trend in the field is to try to develop less invasive, but equally informative, diagnostic tests to possibly replace the more invasive traditional manometry in children.

More to Learn

There is still a great deal to learn about the genetics of bowel motility disorder, and about nongenetic factors that affect motility in children. Treatment options for children with neurogastroenterological disorders include medications that target the GI tract and others that are directed to the brain. 

Treatment should be tailored in the context of the biopsychosocial model. Techniques that in the future are likely to help children with the most severe forms of bowel motility disorders include neuromodulation and selective manipulation of gut microbiota. Regenerative medicine, optogenetics, and the development of more gut-selective medications represent other promising treatments.

The authors concluded that pediatric neurogastroenterology has made remarkable progress in the last decade. The tremendous interest and participation in this symposium provided further evidence for continuing interest in the field, indicating that the future is bright for children with motility and functional bowel disorders.

Building a Model Pediatric Motility Program

Dr. Cocjin and his colleagues at Children’s Mercy are among the leaders in this subspecialty, building one of a handful of programs in the nation utilizing a multidisciplinary approach to care. In fact, two new faculty trained and experienced in neurogastroenterology and motility were recently recruited to join the team, making it one of the largest and most comprehensive in the country focused on diagnosing and treating complex neurogastroenterology issues.

In addition to neurogastroenterology, other disciplines involved in the Children’s Mercy program include otolaryngology, urology, pediatric surgery, physical therapy, psychology, nursing and nutrition. The program provides consultation and follow-up for nearly 1,500 patients, and offers testing services to almost 300 patients annually. 

The Pediatric Motility program also offers access to a comprehensive suite of diagnostic modalities, including detailed pH/impedance studies and a wireless motility capsule that tracks gastrointestinal transit by measuring temperature and pH levels of the gastrointestinal system.

The Biopsychosocial Approach

At Children’s Mercy, traditional medical treatment is combined with a biopsychosocial approach to care, consistent with the recently published proceedings. In fact, a clinical psychologist works closely with the treatment team, ensuring that patients and families have the opportunity to explore the various factors that interact with and contribute to their diagnosis. This helps the team create a comprehensive treatment plan to address each child’s individual needs.

Additional leading-edge therapies being integrated into the Children’s Mercy Pediatric Motility program are biofeedback, hypnosis, acupuncture and alternative and complementary treatment methods.

Sources

1. Proceedings of the 2018 Advances in Motility and in Neurogastroenterology: AIMING for the Future Single Topic Symposium. Ambartsumyan L, Khlevner J, Nurko S, Rosen R, Kaul A, Pandolfino JE, Ratcliffe E, Yacob D, Li BUK, Punati J, Sood M, Rao SSC, Levitt MA, Cocjin JT, Rodriguez L, Flores A, Rosen JM, BelkindGerson J, Saps M, Garza JM, Fortunato J, Schroedl RL, Keefer LA, Friedlander J, Heuckeroth RO, Rao M, El-Chammas K, Vaz K, Chumpitazi BP, Sanghavi R, Matta SKR, Danialifar T, Di Lorenzo C, Darbari A. Journal of Pediatric Gastroenterology and Nutrition: April 13, 2020 - Volume Published Ahead of Print - Issue - doi: 10.1097/ MPG.0000000000002720.

Learn More About Pediatric Neurogastroenterology and Motility at Children's Mercy
 

Jose Cocjin, MD
Chief, Section of Neurogastroenterology and Motility
jtcocjin@cmh.edu
(816) 234-3066
transformpeds.childrensmercy.org

© Copyright 2020 The Children’s Mercy Hospital

In the United States, the most common diagnostic group of chronic kidney disease(CKD) that manifests before age 25 is congenital anomalies of the kidneys and urinary tract (CAKUT) (49.1%). One study suggested that early onset CKD is caused by mutations in any one of more than 200 different monogenic genes.¹

Children’s Mercy Kansas City, recognized as one of the top 10 pediatric nephrology programs in the nation by U.S. News & World Report, is also one of the few to feature a physician with dual expertise in nephrology and genomics. Here, Laurel K. Willig, MD, Pediatric Nephrologist and Medical Director, Genomic Medicine Center, highlights the important role of genomics in the diagnosis, treatment and management of pediatric kidney disease.

Q. HOW IMPORTANT IS GENOME SEQUENCING TO THE DIAGNOSIS AND TREATMENT OF PEDIATRIC KIDNEY DISEASE TODAY?

A. From a clinical perspective, a decade ago most people would have said there’s no reason to do genetic testing on many of these patients. We knew what the diagnosis was, and the results didn’t change the therapy. But, as the cost of sequencing has gone down and genomic technology has become more accessible, it’s becoming much more widely used to confirm inherited nephrology conditions such as polycystic kidney disease (PKD), Alport syndrome and tuberoussclerosis, among others.

Q. WHAT DIFFERENCE DOES SEQUENCING MAKE? HOW IS IT HELPFUL?

A. Genomics and epigenomics can potentially provide patients and families with answers to their diagnostic odyssey. These tests also empower families who are dealing with lifelong disease processes by providing them with informationregarding the type of genetic change they have,their prognosis and potential therapies for certain diseases that can be clinically diagnosed. For example, genetic testing for hereditary glomerulonephritis may allow families to avoid more invasive diagnostic procedures such as renal biopsy. This could also provide important prognostic information as there are dominant, recessive or X-linked forms that may vary, especially in females, in terms of the risk for progression to kidney failure and the development of extra renal manifestations. Recently, newer genotype/phenotype prediction programs have been developed to predict disease severity and also potentially clarify which mutations are likely to be benign.² Finally, researchers have employed exon skipping in mice to help preserve kidney function in those mice with certain types of genetic mutations. This may be on the horizon for certain patients, but they must undergo genetic testing to make this possible.

Q. WHAT TYPES OF GENOMIC TESTS ARE YOU DOING FOR PEDIATRIC NEPHROLOGY? CAN EXTERNAL SITES/PROVIDERS REFER FOR TESTING?

A. Our genome center, which is integrated into thehospital, offers a wide variety of CLIA-certified testing,including microarrays, single and small custom next generation sequencing gene panels, whole exome sequencing and whole genome sequencing. This sequencing can be ordered with additional testing for copy number variation if indicated. We also offer parental testing when indicated for certain scenarios. All clinical testing can be ordered by providers outside Children’s Mercy.

Q. HOW DO YOU INCORPORATE GENOMIC SEQUENCING INTO CLINICAL CARE?

A. Our Pediatric Nephrology Genetics Clinic is a consultative clinic that centralizes care for patients with known genetic disorders that require renal surveillance and follow-up. Currently, we see about 50 to 60 patients per year as part of this clinic, including new patients and those receiving ongoing follow-up. My goal is to incorporate genetic testing into the clinical care model for nephrology patients, helping identify and treat more children with inherited kidney diseases. I believe that a molecular genetic diagnosis, even in the case of a clinically diagnosable disease, is and will become more important for both prognostication and treatment.There are already ongoing trials of treatment options that target only specific types of genetic mutations that lead to the same clinical disease entity. Finally, I try to stay current on the research opportunities for both rare and common genetic kidney diseases, and share information with families when applicable, empowering them to take part in new research if they wish.

Q. HOW DOES THE CLINIC WORK?

A. We systematically utilize genetic testing available through the Children’s Mercy Genomic Medicine Center to diagnose genetic forms of CKD, such as Alport syndrome, tuberous sclerosis, tubulopathies, hereditary hemolytic uremic syndrome, nephrotic syndrome and polycystic kidney disease (PKD). A dedicated genetic counselor is also a valuable team member who consults with each family. The genetic testing we perform allows us to make amore specific diagnosis. With this information, we can monitor and institute early treatment related to other biologic processes that are taking place in association with genetic forms of CKD to achieve the best possible patient outcomes. We also have subspecialty clinics where we see patients with inherited kidney diseases, including cystinosis, tuberous sclerosis and Beckwith-Wiedemann syndrome.

Q. WHAT HAPPENS IF YOU CAN’T PINPOINT A CLINICAL GENETIC DIAGNOSIS THROUGH TRADITIONAL TESTING?

A. Sometimes the genetic testing results families receive aren’t definitive — the answer may lie in a“blind spot” that either we cannot test for with current technology or we don’t know enough about our genomes to understand what the difference means. At Children’s Mercy, we have a unique rare diseases initiative from the Children’s Mercy Research Institute and the Genomic Medicine Center called Genomic Answers for Kids. This hospitalwide genomic research study systematically employs third-generation sequencing and single-cell genomics to uncover more inherited mutations in patients with rare diseases.Ultimately, the program will collect rare disease genomic data and health information from 30,000 children and their families over the next seven years, creating a database of nearly 100,000 genomes. Patients who have undergone appropriate clinical testing could potentially take part in this research if no answer pertaining to their particular disorderhas been found. This testing includes additional transcriptomic and methylation testing in some cases. We have enrolled approximately 25 nephrology patients and their families in this project. Outside physicians can contact the Children’s Mercy Genomic Medicine Center for details.

Q. WHAT RESEARCH PROJECTSIS CHILDREN’S MERCY INVOLVED IN RELATED TO KIDNEY DISEASE AND GENOMICS?

A. Children’s Mercy is a subsite, working collaboratively with the University of Kansas Medical Center, to enroll patients in an NIH-funded biorepository for autosomal dominant polycystic kidney disease (ADPKD) called the Early PKD Observational Cohort (EPOC) study. The purpose ofthe protocol is to expand and follow a longitudinal observational cohort of patients with early-stage PKD and extenda database of clinical information.We have separate funding from the Polycystic Kidney Disease Foundation to apply scRNA-seq to cystic and non-cystic areas of the porcine kidney to identify and characterize subpopulations of cells present in earlydisease, and the biologic pathways that maybe important for cyst initiation in early disease. This project is done in collaboration with Precigen Exemplar, where the pig model was developed and where the tissue is obtained, and The University of Kansas Medical Center, where some of the follow up functional studies are performed.

We also have a BioNexus grant studying the continued widespread use of DNA methylationpatterns in rs-cf DNA as a biomarker of disease severity and progression in congenital anomalies of the kidney and urinary tract. And, in a separate but related project, we are looking at a new disease immunogenomic approach for gaining insight into inflammatory complications in solid organ transplantation, and developing new noninvasive approaches to monitor complications. Finally, we as a nephrology group participate in many multicentered studies such as CKiD, CureGN and NEPTUNE, all of which incorporate genomic testing.

Q. HOW DO YOU SEE GENOMICS SHAPING THE FUTURE OF CLINICAL CARE FOR PEDIATRIC KIDNEY DISEASE PATIENTS?

A. Genetic testing is already becoming such a ubiquitous part of clinical care, it is just a matter of time before it becomes integrated into the standard work-up for pediatric kidney disease. The information this testing provides will guide us to answers for these patients and their families, and targeted, more effective therapies. Soon there may be therapies to treat cystinosis or hereditary glomerulonephritis that depend on the patient’s actual genetic changes, making testing a necessity in order to provide access to these potential groundbreaking treatments. Overall, genomic sequencing will accelerate this process for patients and families.

SOURCES

1. Vivante A, Hildebrandt F. Exome Sequencing Frequently Reveals the Cause of Early-Onset Chronic Kidney Disease. Nat Rev Nephrol. 2016 Mar;12(3):133-46. doi: 10.1038/nrneph.2015.205. Epub 2016 Jan 11.

2. Kamura M, Yamamura T, Omachi K, Suico MA, Nozu K, Kaseda S,Kuwazuru J, Shuto T, Iijima K, Kai H. Trimerization and Genotype-Phenotype Correlation of COL4A5 Mutants in Alport Syndrome. KidneyInt Rep. 2020 Jan 30;5(5):718-726. doi: 10.1016/j.ekir.2020.01.008. PMID:32405592; PMCID: PMC7210609.

Evaluating the timing of postnatal corticosteroid treatment for BPD in a Level IV NICU

In the level IV NICU at Children’s Mercy Kansas City, there is wide variability with regard to timing of steroid treatment among preterm infants with evolving BPD. Some clinicians choose to treat infants who remain intubated on moderately high ventilator settings at around 2 to 3 weeks of life. Others opt to delay treatment until the lungs have had more time to mature and additional efforts to wean from mechanical ventilation have been ineffective.

To examine the association between timing of steroid treatment and outcomes in high-risk preterm infants with evolving BPD, Alain Cuna, MD, neonatologist and Children’s Mercy researcher, and his colleagues, conducted a retrospective cohort study of preterm infants treated with low-dose dexamethasone for BPD.

The study, “Timing of Postnatal Corticosteroid Treatment for Bronchopulmonary Dysplasia and Its Effect on Outcomes,” was published in Pediatric Pulmonology.² Infants treated with dexamethasone at day of life (DOL) 14 to 28 (moderately late group) were compared to infants treated at DOL 29 to 42 (delayed group). Inverse probability of treatment weighting (IPTW) adjusted propensity scores were used to correct for potential confounders. The primary outcome of interest was postmenstrual age (PMA) at discharge.

Identifying determinants of adverse outcomes

Fifty-five infants (25 with moderately late treatment; 30 with delayed treatment) were identified for this research.

The mean age at treatment was 23 days in the moderately late group and 35 days in the delayed group. At time of treatment, infants treated moderately late were more likely to be on high-frequency ventilation (96% versus 47%, P < 0.0001) and had a higher fraction of inspired oxygen (71 ± 18% versus 56 ± 18%, P = 0.005) compared to infants treated later. Despite being the sicker group, moderately later treated infants (14 to 28 days) were discharged at an earlier corrected age compared to infants with delayed treatment (29 to 42 days). Earlier treatment was also associated with fewer days on mechanical ventilation and fewer days on supplemental oxygen, as well as less treatment with repeat or rescue steroids. There was also a trend toward more tracheostomy among delayed-treated infants.² The exact reasons for worse outcomes observed among infants treated later with steroids remain unknown. One possible explanation is that later steroid treatment was less effective than earlier treatment. However, in the study the average time for successful extubation following treatment was similar between the two groups, suggesting that steroids remained equally effective in facilitating extubation whether given earlier or later (Fig).

“Our hypothesis is that the more prolonged exposure to mechanical ventilation among later-treated infants contributed to the worse outcomes seen in this group,” Dr. Cuna said. “In the study, the average difference in time to steroid treatment between the moderately late and delayed groups was 12 days, a not insignificant period of time to remain on mechanical ventilation.”

Together, these findings led Dr. Cuna and his colleagues to conclude that among preterm infants, earlier treatment with steroids can potentially modify the disease trajectory and allow for the sicker cohort to have better outcomes compared to delayed treatment.

Validating Children’s Mercy results nationwide

The research does have limitations since it was a small retrospective study at a single site. However, the paper was in the top 10% of papers downloaded from the Pediatric Pulmonology journal site. This supports our theory that it is a clinically important question with little evidence-based research. Dr. Cuna and his colleagues are seeking to validate their results in a larger patient database. To do so, they are currently utilizing the nationwide database of the Children’s Hospitals Neonatal Consortium, a collaborative of 34 participating level IV NICUs that share data, information and ideas for benchmarking, research and quality improvement initiatives.

They are asking the same questions regarding the timing of corticosteroid treatment and outcomes. This data is currently under analysis. Dr. Cuna anticipates results could be available in the next year, and may provide additional insight and guidance on this important topic.

Learn more about BPD research at Children’s Mercy

Alain C. Cuna, MD, Neonatologist

accuna@cmh.edu • (816) 234-3300

transformpeds.childrensmercy.org

References

1. Watterberg KL, American Academy of Pediatrics. Committee on Fetus and Newborn. Postnatal Corticosteroids to Prevent or Treat Bronchopulmonary Dysplasia. Pediatrics, 2010;126(4):800-808.

2. Cuna A, Lewis T, Dai H, Nyp M, Truog WE. Timing of Postnatal Corticosteroid Treatment for Bronchopulmonary Dysplasia and Its Effect on Outcomes.Pediatric Pulmonology, 2019;54:165–170.

Utilization of telemedicine before and during the pandemic

The Children’s Mercy Kansas City Neurology division provided more than 21,000 pediatric visits in 2019 for everything from epilepsy to pediatric stroke to Tourette syndrome. The division’s team includes more than 100 pediatric neurologists, advanced practice providers, nurses, therapists, imaging specialists, pharmacists, fellows and residents.As word spread that COVID-19 had reached U.S. shores in early 2020, the division’s team quickly began analyzing their capabilities, asking, “How can we provide our patients and their families with the complex medical and psychological care they’ve come to expect, without jeopardizing safety?”Under the leadership of Ahmed Abdelmoity, MD, FAAP, FAES, Director, Division of Neurology, the answer became clear: telemedicine.Prior to the pandemic, Neurology was one of the hospital’s divisions to more actively use telemedicine, but these appointments represented only 6% of its entire operation, while in-person visits represented the remaining 94%. Before COVID-19, patients who utilized telemedicine traveled to satellite clinics where a nurse facilitator helped conduct their exam using a telemedicine robot.With the infectious nature of COVID-19, it was important to rapidly transition to a model where the provider could communicate with the patient in their home. The team was concerned about social distancing, use of the limited supply of personal protective equipment and disease spread, especially for such a vulnerable patient population. All elective surgeries were postponed, except for neuromodulation procedures. Emergency surgeries continued on an as-needed basis.

Prioritizing patients for in-person versus telemedicine visits

Recognizing that in-person visits had to be reserved for only the most complex patients, the Neurology team developed a protocol to address a variety of patient scenarios. This allowed the team to assess each patient individually and assign them to the appropriate visit type. The decision matrix included:

After an initial telemedicine visit, some patients moved forward to an in-person visit due to a high level of anxiety, or a medical issue that required attention in the clinic. By April 2020, the division had shifted 90% of its patients to telemedicine appointments using the Teams application. A team (provider and nursing) also was assigned to address urgent calls, referrals and visits real time.

Patient and provider satisfaction with telemedicine

Admittedly, there was a learning curve with this new process, but as patients and the Neurology providers became more comfortable with it, the added value became apparent. Families liked the safety factor, but also appreciated the convenience of not having to take time away from work for appointments, or drive long distances to the hospital.

During COVID-19, the department monitored patient experience and quality of life metrics. The following questions were only asked of patients after implementation of telemedicine:

Providers were asked the following questions after implementation of telemedicine:

Research opportunities challenge telemedicine assumptions

Another important aspect of the Neurology division’s response to COVID-19 has been the opportunity to develop new research projects related to the pandemic. Led by Dr. Abdelmoity and Jean-Baptiste Le Pichon, MD, PhD, FAAP, Program Director, Neuroscience Research, Children’s Mercy has applied for a two-year, $1 million grant from the Agency for Healthcare Research and Quality called Team Up Against COVID (Telemedicine for Epilepsy to improve Access to care for Minors in Underserved Populations Against Coronavirus).

This research project challenges the assumption that telemedicine is insufficient to properly care for difficult-to-manage patients, such as those on the ketogenic diet.

The grant will evaluate the impacts of the COVID-19 pandemic on children and youth diagnosed with epilepsy in underserved populations, including minorities and low-income urban populations, and will determine the effectiveness of interventions based on telemedicine and increased family/provider engagement.

Aims for this research include identifying barriers to care for at-risk populations as a result of the pandemic; assessing the effectiveness of telemedicine for children and youth with epilepsy; and determining whether short, web-based instructional videos can improve engagement in families of children and youth with epilepsy.

React project assesses concerns regarding care during pandemic

Prior to the pandemic, the division had received funding for the Reaching Out for Epilepsy in Adolescents and Children through Telemedicine (REACT) project. The REACT project is funded by the Health Resources and Services Administration and is a collaboration with the American Academy of Pediatrics.

REACT seeks to increase access to quality, coordinated health care for children and youth with epilepsy, specifically for those residing in rural and medically underserved areas in the state of Kansas. REACT links pediatric epilepsy specialists with primary care providers (PCPs) in these communities, providing remote access through telemedicine technology for patient care and staff education/training.

Though Children’s Mercy had begun deploying REACT in these communities, COVID-19 slowed down implementation of the project. However, the division took advantage of the opportunity, initiating a survey assessing three cohorts of patients: Hispanic rural, non-Hispanic rural and Johnson County, Kansas, residents (a suburban area of Kansas City), to see how these three populations compared regarding changes during the pandemic, and how worried or affected they were about access to their child’s epilepsy care.

Key findings included:

1. Hispanic rural families were more worried about and affected by the pandemic than the other cohorts, followed by non-Hispanic families, then Johnson County residents. For Hispanic families that reported a loss of income, 50% were affected by not being able to pay for their child’s seizure medications, as opposed to 17% of non-Hispanic rural families and 33% of Johnson County families.

2. Regarding mental health and concern that their child with epilepsy was at higher risk for COVID-19, all families from all cohorts reported being worried to some degree. Fifty-six percent of Hispanic rural families were “very or extremely worried” about the risk, as compared to 33% of non-Hispanic rural families and 35% of Johnson County families.

3. With regard to access, again, Hispanic rural families worried at some level (67% for access to primary care provider and 50% for access to epilepsy specialist). However 50% of those were “very or extremely worried” about access to their PCP and 100% of those were worried about access to their epilepsy specialist.

Non-Hispanic rural families were worried at some level (43% for access to primary care and 57% for access to epilepsy specialist). However, 14% of those were “very or extremely worried” about access to their PCP and their epilepsy specialist.

Johnson County families were worried at some level (31% for access to PCP and 35% for access to epilepsy specialist). However, only 4% of those were “very or extremely worried” about access to their PCP and 8% of those were worried about access to their epilepsy specialist.

Utilizing virtual applications to improve educational engagement

An equally important challenge the Children’s Mercy Neurology division faced at the outset of the COVID-19 pandemic was how to safely meet residency and staff educational needs.

Rose Gelineau-Morel, MD, Assistant Program Director, Child Neurology Residency Program, led the transition to a virtual learning environment utilizing the Microsoft Teams application.

Within one week of beginning social distancing, the division began offering an average of four live virtual lectures each week. This was an increase from two weekly lectures prior to COVID-19. Lectures covered diverse topics, including quality improvement and leadership development in addition to clinical neurology, and were made available to all staff, both clinical and nonclinical.

By expanding these lectures to a larger audience and making them more accessible virtually, the division engaged more staff than possible through traditional, in-person educational lectures.

• Pre-COVID-19, an average of seven or eight people attended individual in-person lectures, with 28% of staff reporting they attended at least one lecture each week.
• During COVID-19, those numbers increased significantly, with an average of 22 participants at each lecture, and 79% reporting they attended at least one lecture each week.
• This increased participation continued to grow over time, with 87% of people reporting they attended at least one lecture per week after three months of virtual education.
• Nontraditional presenters also were invited to take part in virtual education, giving other staff members new educational opportunities.

The division also used Teams to store resources for subspecialties within neurology, such as neurometabolic, autoimmune, epilepsy, infectious disease and movement disorders, as well as board preparation materials for residents. Dr. Gelineau-Morel created a “Great Papers” folder, where she included recommended seminal publications, and she added a folder where staff could download and listen to lectures later. Residents created a Continuum Journal club, dividing topics for review and presenting them. Measuring satisfaction with virtual education was an important component of the initiative:

After three months of virtual education, 82.3% of survey respondents reported that they agreed or strongly agreed that virtual education helped them feel more connected to colleagues during this time, and 87.1% wished to continue virtual education.

“Even after we are past COVID-19, I think we will definitely continue some aspect of virtual education,” Dr. Gelineau-Morel said. “This was a great way to engage more people in our educational efforts and help staff feel more connected to one another. And as an organization, accessibility is key. We have providers at multiple locations who can’t always make it to an in-person lecture. Virtual education made it possible for us all to participate, no matter where we were.”

According to JDRF, approximately 1.6 million Americans are living with type 1 diabetes, including about 200,000 youth (less than 20 years old) and more than 1 million adults (20 years old and older).

Type 1 diabetes is a 24/7 disease that requires tight management via continuous glucose monitoring in order to reduce the risk of serious complications, including neuropathy, retinopathy and renal damage. 

Although insulin injections and insulin pumps are both effective treatments for type 1 diabetes, they are also invasive and not well tolerated by all patients, especially children.

Searching for a Better Way to Deliver Insulin

Karen Kover, PhD, researcher with the Division of Endocrinology, Children’s Mercy Kansas City and Associate Professor of Pediatrics, University of Missouri-Kansas City School of Medicine, has been collaborating with Simon Friedman, PhD, Professor, University of Missouri-Kansas City School of Pharmacy, trying to develop a new way to deliver insulin via a photoactivated depot, or PAD. Dr. Friedman originally conceived of the idea for this device several years ago, synthesizing different materials and demonstrating efficacy in vitro. He then enlisted Dr. Kover’s assistance for testing the possible treatment in a diabetic rat model. Initial funding was made available internally through Children’s Mercy and UMKC.

This innovative device has shown great promise in rat models and is the only one of its kind. With the PAD approach, an insulin-containing material is injected into the skin, just like regular insulin, but takes the place of multiple insulin injections each day. The PAD remains under the skin, inactive until a light source from outside the body passes through the skin and stimulates the release of insulin from the depot.

The first-generation PAD designs linked insulin to a polymer via a light-cleaved linker. When a pulse of light from an LED light source was shined directly on top of the injection site, insulin was released. The amount released was proportional to the amount of light applied. 

Research in the diabetic rat model showed that these materials worked to release insulin in the bloodstream and reduced blood glucose. But, it also pointed to several opportunities to improve the device.¹

A 2019 paper published in Molecular Pharmaceutics addressed improvements made to a second-generation PAD, demonstrating effectiveness in the rat model.²

Advancements in Photoactivated Insulin Delivery

Now Dr. Friedman, Dr. Kover and their colleagues have been awarded a $1.5 million R01 grant from the NIH to continue work on this important advancement.

The new grant will help make the technology more reliable to use and easier to manage. For example, the researchers are now creating multiple new PAD materials that eliminate the polymer required in the first-generation materials. These higher-density materials are 90% insulin. 

The researchers also are incorporating new lightcleaved linkers that will release insulin using higher wavelengths of light. This will increase the amount of light that reaches the depot and should improve the ease of insulin release.

Dr. Kover will be closely monitoring these new materials for their ability to control blood glucose in the diabetic rats. She will be looking at issues such as light sources, wavelengths, how well the material is released, how stable it is, and how well it reduces the rats’ blood sugar levels.

In addition, a similar device is being developed that would release glucagon to control low blood glucose levels and will be studied in a rat model of hypoglycemia.

Revolutionizing Treatment for Type 1 Diabetes

As this next stage of research begins, Dr. Kover said the stability of these materials is key to further development. “So far, we’ve only tested the PAD right after the rats have been injected, and we know it does work,” Dr. Kover said. “What we don’t know is how long the insulin will remain viable at the injection site. We need to demonstrate that when you shine the light over the depot for 5 seconds, for example, the same amount of insulin will be consistently released from dose to dose, day after day,” she explained.

Once the researchers have optimized a PAD material and stability can be proven, the next step in the process is to test the PAD in a large animal model, most likely in pigs with type 1 diabetes.

Ultimately, the goal is to create a new and revolutionary method to administer insulin that effectively eliminates most of the injections normally required or the need for an insulin pump. 

An insulin delivery system that is less invasive and more user-friendly has the potential to improve both the quality of life and the health of individuals with type 1 diabetes, especially children, who depend on insulin long term to live. 

© Copyright 2020 The Children’s Mercy Hospital

Learn more about Endocrinology at Children's Mercy.

Karen Kover, PhD, Division of Endocrinology researcher

kkover@cmh.edu • (816) 983-6640

transformpeds.childrensmercy.org

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

References

1 Sarode BR, Kover K, Tong PY, Zhang C, Friedman SH. Light Control of Insulin Release and Blood Glucose Using an Injectable Photoactivated Depot. doi: 10.1021/acs.molpharmaceut.6b00633. Mol. Pharmaceutics 2016, 13, 3835−384.

2 Sarode BR, Kover K, Friedman SH. Visible-Light-Activated High-Density Materials for Controlled in Vivo Insulin Release. Mol Pharm. 2019 November 04; 16(11): 4677–4687. doi:10.1021/acs.molpharmaceut.9b00806.

Narcolepsy is a lifelong neurological disorder characterized by excessive daytime sleepiness, cataplexy, sleep-related hallucinations and sleep paralysis.

Typical onset of this condition may occur anytime between the ages of 10 and 20, with the peak age of identification around 15 years old. Some researchers believe that narcolepsy is under-diagnosed in children.¹ 

While there are medications to treat narcolepsy, these patients may have substantial medical and psychological comorbidities. In children, comorbidities include rapid weight gain, precocious puberty and a significant burden of illness related to mental health and school performance.

Wake Up Narcolepsy Funds Pediatric Study

David Ingram, MD, a pediatric sleep specialist and researcher with Children’s Mercy Kansas City and a board member for the advocacy organization Wake Up Narcolepsy, along with Lindsay Jesteadt, PhD, Claire Crisp and Stacey Simon, PhD, conducted a study to report on the primary challenges of youth, parents and physicians related to narcolepsy; assess perception of clinical care; and elicit feedback regarding the ideal configuration of care.

Their research was recently published in the Journal of Clinical Sleep Medicine and was funded by Wake Up Narcolepsy.² They utilized the organization’s database to conduct an anonymous internet survey of children/ adolescents ages 12-22, parents of children with narcolepsy and sleep physicians. Separate youth, parent and provider versions of the survey included both multiple-choice and open-ended questions.

Youth and Parents Identify Challenges

In all, 35 youth and 116 parents completed the surveys. Youth and parents rated these symptoms as the most common and problematic: 

1. Daytime sleepiness

2. Disturbed nighttime sleep

3. Mood difficulties 

Youth and parents identified these primary psychosocial concerns as substantial challenges: 

1. Difficulty focusing/memory

2. Difficulty with schoolwork

3. Worry/anxiety

Youth and parents commonly reported these behavioral strategies related to narcolepsy: 

1. Scheduled bedtime/wake time

2. Daytime naps

3. Exercise and diet

Physicians Cite Different Concerns

Thirty sleep medicine physicians completed the same survey. Interestingly, the study identified a contrast between concerns for youth/parents and physicians, with physicians citing medication side effects and getting a driver’s license as the greatest challenges for their patients. Physicians found the most used and helpful medications to be traditional stimulants, sodium oxybate and modafinil/armodafinil.

Preference for Multidisciplinary Care

Despite the significant medical and psychiatric comorbidities associated with narcolepsy, traditionally, most pediatric hospitals provide care for these patients at individual specialist appointments, rather than in a multidisciplinary clinic setting. 

As part of this research, Dr. Ingram and his colleagues set out to determine if this care model is meeting the needs of pediatric narcolepsy patients and their families, eliciting feedback regarding the ideal configuration, features, services and structure of state-of-theart family-centered care.

Their findings were consistent with a recent survey of patients with hypersomnia, which suggests that a sizeable proportion of patients’ symptoms are not managed by medications alone. More than 90% of patients utilize nonpharmacologic therapies.³

Specific findings of Dr. Ingram’s survey included:

• Youth and parents preferred clinic visits every three to four months in a multidisciplinary clinic including nursing, psychology and nutrition, lending support for a biopsychosocial framework in caring for pediatric narcolepsy patients. 

• Additional resources from support groups, family education days and family retreats were also highly rated as potentially beneficial.

Investigating Treatment Effectiveness

Based on this research, the Children’s Mercy Sleep Center has developed a Narcolepsy Pre-Visit Clinic Worksheet that patients and families complete before their appointment. This allows the patient and family to list all their concerns so the team can address them efficiently.

Dr. Ingram and his colleagues also are in the process of completing a second stage of this research focused on treatment. Important aspects addressed include medications and lifestyle modifications, such as sleep hygiene, diet and exercise. Dr. Ingram anticipates this study will be published in an academic medical journal in 2021.

In addition, the Children’s Mercy team is considering establishing a multidisciplinary narcolepsy clinic, with patient visits integrating sleep specialists, a behavioral psychologist, nutrition services and social work rather than scheduling separate appointments.

Learn more about Sleep Medicine at Children's Mercy.

David Ingram, MD, Pediatric Sleep Specialist

dgingram@cmh.edu • (816) 983-6355

transformpeds.childrensmercy.org 

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

References
 

1. Wake Up Narcolepsy website:  https://www.wakeupnarcolepsy.org/ about/what-is-narcolepsy/. Accessed June 26, 2020.
 

2. Perceived Challenges in Pediatric Narcolepsy: A Survey of Parents, Youth, and Sleep Physicians. Ingram D, Jesteadt L, Crisp C, Simon SL. Journal of Clinical Sleep Medicine. September 8, 2020. doi: doi. org/10.5664/jcsm.8774.
 

3. Behavioral Sleep Medicine Services for Hypersomnia Disorders: A Survey Study. Neikrug AR, Crawford MR, Ong JC. Behavioral Sleep Medicine 15(2):1-14. January 2016.

One of the important nonphysiologic factors influencing referral is parental concern about the psychological effects of short stature on the child.^1,2 Some parents believe that short stature will lead to low self-esteem, poor school performance or difficulties with peer relationships. These attitudes might influence decisions about starting growth-promoting therapies, administration strategies and length of the treatment.³ Finkelstein et al. showed that physicians were 40% more likely to recommend growth hormone treatment for a child when the family showed strong interest in the treatment.⁴

Comparing Attitudes of Parents Regarding Short Stature

Do views regarding short stature differ between parents who are referred to and seek care from a pediatric endocrinologist and parents who are not referred? And do the attitudes of these two groups change over time?

Those are the questions Max Feldt, DO, Pediatric Endocrinologist, Children’s Mercy Kansas City, and his colleagues addressed when comparing attitudes among parents whose children were referred to endocrinologists for short stature to parents of children with heights <10th percentile presenting to their pediatricians for a regular visit who were not referred. Results were published in the May 2020 edition of the Journal of Pediatrics.⁵

Some of the data from the referred cohort have previously been published, but nothing has been published about their attitudinal changes over time.⁴ To explore this uncharted territory, Dr. Feldt surveyed these same groups of parents (both referred and controls) 15 years later. In addition to asking the parents about the child’s final height and growth-promoting therapy, he also studied the factors that predicted changes in parental attitudes about short stature, from baseline to follow-up.

Survey Methods

At baseline (1993-1994), parents were surveyed about their attitudes regarding their children’s height. The researchers compared parents of children (aged 4-15 years) referred to endocrinologists (referred,154) with those of children with heights <10th percentile seen by pediatricians during regular visits (control, 240). At follow-up (2008-2009), 103 control and 98 referred parents completed a similar survey. Dr. Feldt then made a logistic regression analysis to observe changes in perception, including:

• Self-esteem
• Treatment by peers
• Ability to cope with current height

At baseline, parental perception of the impact of short stature on their children was worse in the referred group than in the control group.

Endocrinology Referral Associated with Psychosocial Improvement at Follow-up

At follow-up, referred parents were 3.8 times more likely to report improvement in their child’s self-esteem, 2.4 times more likely to report improved treatment of their child by peers, and 5.7 times more likely to report improvement in their child’s overall ability to cope with height than were unreferred parents.

Referral to an endocrinologist was a better predictor of psychosocial improvement than was final adult height or change in height since the original study. Being treated was not associated with a perception of fewer psychosocial problems. Untreated control and referred children gained considerably in height SD score over 15 years, reaching similar adult heights.

Impact on Clinical Care

The remarkable finding in this study was that the parents of children who were referred to an endocrinologist were more likely to perceive an improvement in their child’s psychological outcomes than did the parents of children who were not referred, even when controlling for whether the child received treatment, or the child’s final adult height, or change in height since baseline. This finding was true for measures of self-esteem, treatment by peers and ability to cope, and suggests that, for at least some parents, referral to an endocrinologist might be therapeutic in itself.

“Often, parents focus on stature when their child is otherwise healthy,” Dr. Feldt said. “At Children’s Mercy, we recommend having these conversations and addressing questions regarding stature with families and patients separately. This is an important part of the medical care we provide, preserving the child's self-esteem. This study gives us the data to reassure parents their attitudes may change over time, and helps the family and the endocrine provider to make better medical decisions on the child’s behalf.”

Learn More About Endocrinology at Children's Mercy

Max Feldt, DO, Pediatric Endocrinologist

mmfeldt@cmh.edu • (816) 960-8820

transformpeds.childrensmercy.org

References:

Idiopathic Short Stature: Decision Making in Growth Hormone Use.Maheshwari N, Uli NK, Narasimhan S, Cuttler L. Indian J Pediatr 2012;79: 238-43.2

Patient, Physician, and Consumer Drivers: Referrals for Short Stature and Access to Specialty Drugs. Cuttler L, Marinova D, Mercer MB, Connors A, Meehan R, Silvers JB. Med Care 2009;47:858-65.3.

A National Study of Physician Recommendations to Initiate and discontinue Growth Hormone for Short Stature. Silvers JB, Marinova D, Mercer MB, Connors A, Cuttler L. Pediatrics 2010;126:468-76.4.

Patient Attitudes and Preferences Regarding Treatment: GH Therapy for Childhood Short Stature. Finkelstein BS, Singh J, Silvers JB, Marrero U, Neuhauser D, Cuttler L. Horm Res 1999;51:67-72.5.

Parental Concerns on Short Stature: A 15-Year Follow-Up. MuranoMC, Feldt MM, J Pediatr 2020;220:237-40.

Neonatologists routinely face the challenge of caring for extremely low birth weight babies (<28 weeks’ gestation) at risk for the lethal bloodstream infections causing sepsis and necrotizing enterocolitis, or NEC. Currently, the most common practice is to give these infants empiric antibiotics at birth and for the next two to three days as clinicians await microbiology results. However, there are no data to support or refute this practice, and numerous studies have shown that >95% of extremely low birthweight infants receiving empiric antibiotics do not have early onset sepsis. In some cases, antibiotics may actually disrupt the delicate gut microbiome and increase the riskof infection. The challenge is to determine which infants can safely avoid antibiotics and whether antibiotics interact with genetic and microbial risk factors to increase the risk of severe diseases.

Identifying Determinants of Adverse Outcomes

The NICU Antibiotics and Outcomes, or NANO trial, is an NIH/NICHD-funded multicenter randomized controlled trial. Mike Morowitz, MD, with the Universityof Pittsburgh Medical Center Children’s Hospital, is the trial’s principal investigator.¹ The NANO trial challenges whether empiric antibiotics at birth may increase the risk of adverse outcomes, such as NEC in extremely low birth weight infants. The Children’s Mercy Kansas City Level IV NICU is one of 14 sites participating in this study. Though the NANO trial includes funding to collect both genomic and microbial specimens from these babies, it does not include funding to perform the genomic and microbial analysis of them.

Venkatesh Sampath, MBBS, MRCPCh, neonatologist and Medical Director of the Donald Thibeault Lung and Immunology Laboratories at Children’s Mercy, recognized the importance of genetic and microbial analysis to the NANO trial. In a separate grant, March of Dimes is funding a three-year study that will provide for genomic and microbial analysis to supplement the NANO trial’s core clinical activities. The goal of the March of Dimes trial is to identify genomic and microbiome determinants of adverse outcomes among infants enrolled in the NANO trial.²

Dr. Sampath has previously demonstrated that deleterious mutations in the toll-like receptor (TLR) family of innate immune genes impact susceptibility to NEC and sepsis. He will lead the genomic aspect of this work, while Dr. Morowitz will focus on profiling the infant gut microbiome.

“This March of Dimes study gives us aunique opportunity to confirm some of thegenetic data we have regarding NEC andsepsis, identify new genetic risk factors,and determine how these genetic riskfactors interact with the gut microbiomeand early antibiotic use to increase the riskof NEC and sepsis.” – Dr. Sampath

Sequencing Genetic Samples 

The hypothesis for the March of Dimes-funded study is to test whether specific TLR gene mutations in extremely low birth weight infants increase vulnerability to late onset sepsis and NED by amplifyingthe consequences of antibiotic-induced gut dysbiosis. During the pilot phase of the study, Dr. Sampath is conducting exome sequencing for 350 specimens previously collected from infants in the Children’s Mercy NICU and other centers, and that have been held in a biorepository. Collection of 20 out of an anticipated 300 DNA samples from infants participating in the NANO trial also will be completed during this phase, as well as initial analyses of TLR-related exome sequences for 10 infants.The sequencing will be performed in conjunction with the Children’s Mercy Genomic Medicine Center, led by Tomi Pastinen, MD, PhD, Director, and Emily Farrow, PhD, CGC, Director, Laboratory Operations. Dr. Sampath’s ongoing NIH-funded study³ has identified the SIGIRR gene as a potential risk factor for NEC, and this study will seek to detect other possible genetic targets. Over the course of the March of Dimes study, genetic samples from additional neonates recruited into the NANO trial will be added to the biorepository, and will be sequenced.

Exploring Genetic and Microbial Connections

Dr. Sampath already is working on the pilot portion of this trial, exome sequencing 350 babies for specific TLR genetic mutations. Upon approval from March of Dimes, he will continue analyzing these DNA samples.

The goal for the March of Dimes-funded study is for Children’s Mercy to complete genetic analyses for morethan 700 babies, while Dr. Morowitz and his team analyze the microbiome of these infants. Their work will result in one of the most far-reaching studies in neonatology exploring the genetic and microbial connections to NEC and sepsis in extremely low birth weight babies.

Determining Which Infants Antibiotics May Help

Dr. Sampath is working to understand why some preterminfants develop NEC and some do not by identifying pathogenic TLR pathway variants via exome sequencing.This data will be used to study the relationship between genetic risk factors, the gut microbiome and antibiotics.The results may aid in the development of genetic and microbiome tools to screen infants at risk for NEC and sepsis in the NICU, instituting precision measures to help physicians determine which infants are at highest risk for these life-threatening complications and may benefit from avoidance of antibiotics or altering the microbiome using probiotics and other therapies.

According to a 2017 study published in Nutrition Clinical Practice, about 40% of all individuals with feeding tubes are children.¹

Although tube feeding saves the lives of children who do not eat orally, chronic tube feeding can be a burden to patients, caregivers and families, making the transition to oral feeding an important goal.

Existing treatment options for this transition include outpatient, inpatient and day treatment programs. Outpatient treatment delivered by a multidisciplinary team during clinic visits is the most widely available.

NIH Funds Study on Weaning Patients from Tube to Oral Feeding

Ann M. Davis, PhD, MPH, ABPP, Director, Center for Children’s Healthy Lifestyles & Nutrition at Children’s Mercy Kansas City and Ralph L. Smith Professor of Pediatrics at the University of Kansas Medical Center, is leading iKanEat, a novel interdisciplinary outpatient protocol for transitioning children from tube to oral feeding.

The five-year study is funded by the National Institutes of Health. Sarah Edwards, DO, Director, Multidisciplinary Feeding Clinic, and Jose Cocjin, MD, Chief, Section of Neurogastroenterology and Motility, are conducting the study and enrolling patients at Children’s Mercy Kansas City.

Study sites began recruiting patients in August 2019, with the goal of enrolling 72 patients total. To date, Children’s Mercy has enrolled five patients, the largest number of any participating institution.

iKanEat Protocol Effective

Previous data suggest the iKanEat protocol is effective for transitioning tube-fed children to eating by mouth. The original iKanEat study included two medications: amitriptyline, an antidepressant; and megestrol, an appetite stimulant.

The team’s work demonstrated that amitriptyline is not a necessary component of the protocol, because all children who completed the protocol consumed 100% of their calories orally post treatment, regardless of whether they received amitriptyline or placebo. Amitriptyline was subsequently removed from the protocol.²

The current protocol is a randomized controlled trial of megestrol compared to placebo. It is assessing whether a four-week course of megestrol improves outcomes within the iKanEat protocol.

Concurrently Examining Gut Microbiota  

Little is known about the gut microbiota of children who transition from formula to oral feeding. That’s why Dr. Edwards saw this as an opportunity to determine how the gut microbiome adapts to changes in diet over time in children who transition from commercial or blended formulas to an oral diet.

Dr. Edwards has received supplemental funding from the Center for Healthy Lifestyles & Nutrition and the Children’s Mercy Division of Gastroenterology to examine this important question. This arm of the research is running concurrently with the NIH study.

None of the children enrolled in the NIH study will change their current dietary formulations, but the gut microbiome aspect of the study hypothesizes that the transition to oral feeding will increase the variety of foods consumed orally, leading to a more diverse gut microbiome by week 24. It also theorizes that children on a blended diet formula at week zero will have a more diverse microbiome than children on a commercially prepared formula prior to transitioning to oral feeding.

This research could add to general knowledge about how the gut microbiome adapts to changes in diet over time in children who transition from commercial or blended formulas to an oral diet.

Transitioning From Tube Feedings

The iKanEat protocol combines outpatient clinic and telemedicine visits, providing benefits to patients and families including reduced risk of complications, such as infection, and improvements in quality of life.

The 24-week iKanEat intervention includes four in-person clinic visits at participating sites and 12 remote telemedicine visits. Stool samples for the microbiota arm of the study are collected at the in-person visits.

Remote sessions utilize the videoconferencing app Zoom on a computer or tablet, or are conducted over the phone. During weeks 1-10, the caregiver works with a feeding specialist on the remote feeding calls to improve the child’s feeding skills.

At week 10, the child begins to transition off tube feedings. The child is given either the megestrol or placebo to take at this time. The caregiver reduces the child’s tube feedings by 10% each day over 10 days, until the child is completely off tube feeding.

Potential to Transform Clinical Care

The iKanEat study will conclude in 2023. Though its primary purpose is to investigate the role of the appetite stimulant megestrol, according to Dr. Edwards, the outpatient/remote access weaning program being used is unique and could lead to changes in treatment protocols for children transitioning from tube to oral feeding.

The supplemental study regarding the gut microbiome may shed new light on the effect of the transition from tube to oral feeding on the gut microbiome.

Learn More About Gastroenterology at Children's Mercy 

Sarah Edwards, DO, Medical Director, Multidisciplinary Feeding Clinics

edwards1@cmh.edu • (816) 234-3066

transformpeds.childrensmercy.org

Ann M. Davis, PhD, MPH, ABPP, Director, Center for Children’s Healthy Lifestyles & Nutrition

amdavis2@cmh.edu • (816) 302-8588

transformpeds.childrensmercy.org

References 

1.  Prevalence of Home Parenteral and Enteral Nutrition in the United States. Mundi MS, Pattinson A, McMahon MT, Davidson J, Hurt RT. Nutr Clin Pract. 2017 Dec;32(6):799-805. doi: 10.1177/0884533617718472. Epub 2017 Jul 17.

2. iKanEat: Study Protocol for a Randomized Controlled Trial of Megestrol for Children with Feeding Problems. Edwards S, Hyman PE, Mousa H, Bruce A, Cocjin J, Dean K, Fleming K, Swinburne Romine R, Davis AM. Submitted to BMJ Open.

All patients with changes or concerns during their cardiac work-up are seen in the oncology clinic by a cardio-oncology specialist. This approach of having all specialists come to the patients in their oncology home provides crucial continuity of care, including long-term monitoring as part of the survivorship program.

Acute Cardiac Issues During Therapy

During the administration of chemotherapy, approximately10%-20% of patients experience acute cardiac issues, such as decreased cardiac function, heart dilation or rhythm problems or effusions. Cardio-oncologists work closely with oncologists to determine the best course of action: continue therapy, alter the dose or discontinue the drug.

The risks vary based on the chemotherapy regimen employed. The toxicity of anthracyclines is affected by the number of rounds and the specific dose given. Children’s Mercy cardio-oncologists monitor the cumulative exposure to these drugs while considering risk stratification recommendations developed by the Children’s Oncology Group.

Dr. Fulbright is the co-chair of the Children’s Oncology Group Survivorship and Outcomes Cardiovascular Task Force. This group reviews the most recent literature on late effects and releases updated recommendations every five years. Children’s Mercy considers these recommendations to help stratify patients according to their risk level for developing heart failure.

Long-term Concerns

Effects from chemotherapy can occur soon after completion of therapy, but cardiac late effects become more prevalent as a person ages, up to 10 to 20 years after therapy is complete. They often emerge as left ventricular or systolic heart failure. Rhythm issues such as bradycardia and QT prolongation also can occur. Hypertension is a modifiable risk factor for the development of heart failure, so blood pressure must be carefully monitored during both the acute and chronic phases. A dietician meets with families at every survivorship visit to coach families on living a healthy lifestyle, emphasizing good nutrition and exercise.

If a patient receives radiation to a field that includes the heart, scarring can occur that leads to valve issues, heart failure or a restrictive physiology that can affect function. Abnormal lipids also can occur as a result of the abdominal radiation. Radiation patients experience a higher risk of coronary issues and myocardial infarction than those who did not receive this type of treatment.

Improving Detection of Late-Onset Cardiac Dysfunction 

Children’s Mercy is an early adopter of strain imaging with echocardiogram. While the technology is not new, its use in cardio-oncology is recent, thanks to studies that have evaluated its efficacy in the detection of chemotherapy-associated cardiotoxicity.

For example, a recent prospective multicenter study by Sawaya, et al., demonstrated that global longitudinal strain (GLS) <19% was predictive of subsequent cardiotoxicity and was present in all patients who later developed symptoms of heart failure. Another study, by Negishi, et al., similarly showed that an ≥11% relative reduction in GLS was predictive of subsequent trastuzumab-associated cardiotoxicity.

These demonstrated outcomes led Children’s Mercy to implement strain imaging for its predictive capabilities, with the aim of determining whether earlier intervention can lessen disease burden.

Sanket S. Shah, MD, pediatric cardiologist at Children’sMercy, led a study that compared echocardiographic methods, cardiac MRI and cardiac biomarker testing in adolescent cancer survivors. The study was published in Echocardiography.

Early Patient Tracking Suggests Improved Outcomes

Patients are referred from primary oncology teams, bone marrow transplant physicians, primary care physicians, and from Survive and Thrive, the Children’s Mercy survivorship clinic. Of those tracked to date, patients were evaluated for valvular dysfunction, concern for arrhythmia, global hypokinesis and decreased left ventricular function. One-third of patients with a decrease in left ventricular dysfunction required only close monitoring and two-thirds were started on an ACE inhibitor, which led to improvement or stabilization of function. The team is formalizing a process for tracking all patients evaluated in the cardio-oncology clinic.

The Future of the Program

Dr. Fulbright and Dr. Shah recently presented a multidisciplinary grand round to help increase regional awareness of the program. They work closely with the University of Kansas Health System (UKHS) to transition pediatric cancer survivors to a team that includes adult cardiologists who have a specific interest in caring for cancer patients. As the cardio-oncology program continues to expand and evolve, the goal is to work more closely with UKHS to expand research efforts and evaluate long-term outcomes for survivors. A registry of adult childhood cancer survivors, established in 2016, will aid in this effort. In addition, Children’s Mercy is beginning to focus on collaboration with other pediatric centers, as they create similar programs, to share protocols and learn from successes.

Sources

1. Sawaya H, Sebag IA, Plana JC, et al. (2012) Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab. Circ Cardiovasc Imaging 5:596–603.

2. Negishi K, Negishi T, Hare JL, Haluska BA, Plana JC, Marwick TH (2013) Independent and incremental value of deformation indices for prediction of trastuzumab-induced cardiotoxicity. J Am Soc Echocardiogr 26:493–498.

3. Shah SS, McClellan W, Knowlton JQ, Mehta J, Goudar S, Ferguson A, Sherman A, Shirali G, Fulbright J. Medium-term assessment of cardiac function in pediatric cancer survivors. Comparison of different echocardiographic methods, cardiac MRI and cardiac biomarker testing in adolescent cancer survivors. Echocardiography.2017 Feb; 34(2):250-256. doi: 10.1111/echo.13418. Epub 2016 Dec 20.

National Initiative Reveals Need for Pediatric Emergency Planning 

National Pediatric Readiness Project is a multiphase quality improvement initiative to ensure that all U.S. emergency departments (EDs) have the essential guidelines and resources in place to provide effective emergency care to children. It’s a partnership between the federal Emergency Medical Services for Children (EMSC) Program, the American Academy of Pediatrics (AAP), the American College of Emergency Physicians (ACEP) and the Emergency Nurses Association (ENA). Of the 4,146 EDs that participated in the 2013 National Pediatric Readiness assessment, only 47% responded that they have a disaster preparedness plan in place that addressed the unique needs of children.

Pediatric Social and Physiologic Factors that Increase Vulnerability

Different age groups of children will require different services. Young children have an increased vulnerability in disasters, given their social dependency for care on adults who may also be victims. In addition, their unique physiology can predispose them to injury and exposures that may not be as significant in adult patients.

Specific physiologic vulnerabilities of young children include:

• Lower circulating blood volume
• More systemic side effects from fluid loss (caused by vomiting/diarrhea/burns)
• Increased ratio of head and body surface area to mass predispositions to head injuries and hypothermia with exposure
• Immature immune systems and potentially incomplete or unknown vaccination protection

The Role of Orthopedics in an Earthquake 

The most common injuries following a significant earthquake event are fractures, traumatic wounds (potentially associated with fractures) and head injuries due to collapsing structures. A case study of the 2010 Haiti earthquake illustrates the key role of orthopedics in a disaster.¹ The Swiss Disaster Medical Assistance Team that responded to the earthquake recorded its experience in Port-au-Prince for 43 days:

• 471 of 796 treated patients were under age 18. Each was assigned to a surgical group or a medical group based on the medical care required.
• Patients were evaluated on when they presented for care – either the early period (first 10 days after disaster) or the late period (days 11-43 post disaster).
• 134 of 147 early patients (91%) were surgical, and 88% of the surgical patients required orthopedic care.
• 110 of 324 late patients (34%) were surgical, with the remaining 214 (66%) medical.

Other studies of earthquake-induced mass casualty events led to similar findings, with a massive surge of orthopedic injuries in the pediatric population requiring surgical care within the first 10 days. These studies underscore the need for preparation and rapid deployment of pediatric orthopedic providers in this specific disaster scenario.

Children's Mercy Increases Its Disaster Readiness

Children’s Mercy is designated as a Level 1 Pediatric Trauma Center by the state of Missouri. The hospital is increasing its disaster preparedness as it goes through the American College of Surgeons (ACS) pediatric trauma center verification process. Such preparation is vital for the population located in the large geographic area around Kansas City served by the hospital. This area’s primary disaster risk is from severe weather outbreaks that can produce damaging tornadoes. But Children’s Mercy is required, as are all hospitals, to take an “all-hazards” approach to disaster preparation, so that the hospital can provide the region the services required to cope with any disaster or mass casualty event that may occur.

Profile of a Recent Disaster: The Joplin Tornado²

• >750 injuries, >150 fatalities
• Children’s Mercy (150 miles north of Joplin) received 10 patients in transfer
• Traumatic brain injuries were the most common reason for transfer, followed by orthopedic and maxillofacial injuries
• 7 out of 10 patients required surgery
• 8 out of 10 patients required PICU hospitalization
• Average length of stay: 19.4 days (14 hours to 94 days)

Disaster Planning Gets National Attention 

In 2019, Dr. Sinclair presented at the Presidential Symposium of the American Academy of Orthopaedic Surgeons (AAOS) meeting on the importance of pediatric disaster planning. He co-chaired a two-hour seminar on this important topic during the Pediatric Orthopaedic Society of North America (POSNA) virtual meeting that opened in May 2020. He has co-authored a chapter on this topic that will be included for the first time in Orthopaedic Knowledge Update (OKU): Pediatrics 6. This resource should be available in spring 2021 to help other pediatric centers develop effective disaster management plans.

Learn More About Disaster Planning at Children's Mercy 

Mark Sinclair, MD

mrsinclair@cmh.edu • (816) 234-3693

transformpeds.childrensmercy.org

References:

1. Gamulin A, Armenter-Duran J, Assal M et al. Conditions Found Among Pediatric Survivors During the Early Response to Natural Disaster: A Prospective Case Study. J Pediatr Orthop 2012;32:327-333.

2. Watts J. Pediatric Injuries Treated at a Level 1 Trauma Center after an F5 Tornado. Pediatr Emerg Care 2018;34:783-786.

The Neurology-Rheumatology Combined Clinic now includes three physicians: Tyler Allison, MD, neurologist; Cara Hoffart, DO, rheumatologist; and Julia Harris, MD, rheumatologist. Together they see a highly complex patient population with autoimmune conditions that affect the central nervous system (neuroimmune disease). With these rare pediatric diseases, the team is faced with a lack of data and trials to guide treatment plans. They often must extrapolate information from the adult literature and case reports and series. The team members combine their knowledge and provide care based on the most current evidence-based guidelines from each subspecialty.

On clinic days, patients are seen concurrently by a neurologist and rheumatologist. Each performs a thorough physical exam, and together they listen to input from the patient. By the end of the visit, the team creates a unified plan of care. The parents and patients appreciate the combined visits, which minimize time and transport for the families. More importantly, the patients feel confident in the plan of care, having heard it from both the neurologist and rheumatologist at the same time. They also better understand the treatment rationale and are more engaged in the management of their own illnesses.

Some conditions treated in the clinic: 

• Adenosine deaminase 2 (ADA2) deficiency
• Autoimmune ataxia
• Autoimmune encephalopathies/encephalitides; including anti-NMDA receptor encephalitis
• Chronic inflammatory demyelinating polyneuropathy (CIDP)
• CNS lupus
• CNS sarcoidosis
• CNS vasculitis
• MOG-IgG-associated inflammatory disease
• Myasthenia gravis
• Neuromyelitis optica ± spectrum disorder
• Opsoclonus-myoclonus syndrome

Pooling Data on Rare Conditions Via Brainworks

BrainWorks, an international repository created at The Hospital for Sick Children, was established to improve the understanding of inflammatory diseases of the brain and spinal cord. This multisite consortium of neuroimmunology patients provides an avenue for pediatric centers to pool data on rare diseases as a way to develop the most effective diagnostic and treatment approaches using evidence-based medicine.

Dr. Allison is the site principal investigator for BrainWorks for Children’s Mercy. The team is a significant contributor to the registry due to the large volume of patients who meet criteria for inclusion in the database. The data they contribute will eventually help foster research that will lead to new guidelines and protocols for diagnosing and treating pediatric patients instead of extrapolating from adult patient data and case reports.

Increasing Clinic Capacity and Capabilities 

For the first four years, clinic capacity was 24 visits per year. Today the clinic handles approximately 84 patient visits per year. Due to increased demand, plans are in place to expand appointment availability to be able to handle more than 120 patient visits per year. The team is also making plans to expand capabilities. For example, approximately 80% of clinic patients are living with a chronic illness, which can be difficult to process. Psychologists will soon be integrated into the clinic to provide mental health support, and discussions are underway to determine ways to provide strong psychosocial support to families.

Patient Story

When an 8-year old child presented to Children’s Mercy for a stroke, the care team was focused on identifying the underlying cause. The patient recovered well from the first stroke in a short period of time, but even after a significant work-up, the team was unable to find the underlying reason. A month later, the patient had a second stroke, which led to a brain biopsy diagnosis of primary CNS vasculitis. Dr. Harris and Dr. Allison worked together in the Neurology-Rheumatology Clinic to provide the patient with the best evidence-based treatments available, based on BrainWorks protocols. After several months of treatment, the patient relapsed, suffering a third stroke. While scant medical evidence existed to specify the next step in therapy the team’s ongoing collaboration in the Neurology-Rheumatology Clinic led to treatment options that have managed this rare disease for the past two to three years without any signs of relapse.

Learn More About the Neurology-Rheumatology Combined Clinic at Children's Mercy

Tyler Allison, MD

Director, Neurology-Rheumatology Clinic 

tallison@cmh.edu / (816) 302-3331

Julia Harris, MD

jgharris@cmh.edu / (816) 302-3686

Cara Hoffart, DO

cmhoffart@cmh.edu / (816) 302-3686

Sexual development involves a complex interplay among a variety of hormones, signaling pathways and crosstalk within the hypothalamic-pituitary-gonadal axis, as well as in other target tissues. Estimates suggest that more than a thousand genes are involved in testicular development, and a similar number of genes affect ovarian development. Add in a range of nongenetic causes that influence sexual development, and the diagnostic challenges become clear.

The Importance of Evaluation and Diagnosis

Identifying and managing the underlying cause of ambiguous genitalia is crucial to long-term health. For example, detection of disease-causing variants in NR5A1, NR0B and the multiple genes that cause congenital adrenal hyperplasia could potentially circumvent adrenal crises, including the risk of sudden death. Certain types of cancer, such as Wilms tumor, are affected by variants in WT1. For patients with this variant, periodic screening for malignancy will be necessary. In other patients, the underlying molecular cause could lead to prognostic potential for fertility and the risk of gonadal tumors.

About the GUIDE Clinic 

The GUIDE (Gynecology/Genetics/Genomics, Urology, Interdisciplinary, Developmental, Endocrinology) Clinic, which opened in 2008, provides complete care for patients with all forms of differences of genital development from birth to age 21.

Study Framework

Starting with the GUIDE Clinic’s retrospective and prospective data repository, which contains molecular data on every patient seen since the clinic opened in 2008, Dr. Jacobson and the GUIDE team conducted a retrospective chart review to determine how many undermasculinized male patients received a molecular diagnosis. The team has continued to apply stepwise genetic testing to all undermasculinized patients with DSDs who present to the interdisciplinary GUIDE Clinic. External masculinization scores were recorded. Then patients underwent progressive testing:

• Karyotype
• Individual gene testing
• Microarray
• Panel testing
• Whole-exome sequencing

A total of 60 undermasculinized male patients were seen in the clinic during the study period, from July 2008 to December 2016.

Diagnostic Algorithm 

Dr. Jacobson developed an algorithm to support the diagnosis of patients with ambiguous genitalia. To see the algorithm, please visit https://doi.org/10.1210/endocr/bqz015. 

Results 

The key finding from the study identified:

Of the 46,XY patients who underwent all available genetic testing, 18 of 28 (64%) received molecular diagnoses.

This study finds that 18 of 28 (64%) of undermasculinized 46, XY individuals who underwent all available testing achieved molecular diagnoses.

This percentage is comparable to the diagnosis rate in masculinized females undergoing conventional testing during the same time frame.

The Children’s Mercy GUIDE Clinic diagnosis rate is considerably higher than that reported in the numerous studies on DSD, which nearly always show a diagnosis rate below 50%.

Dr. Jacobson and the GUIDE team outlined the details of their study in a paper that has been accepted for publication by Endocrinology.

Next Steps 

Although Dr. Jacobson’s work has already increased the rate of molecular diagnoses, many patients are still left with no diagnosis, leaving them at risk for serious complications. Her team hopes to eventually include whole-genome sequencing through the Children’s Mercy Genomic Medicine Center as a way to further increase diagnosis rates for these patients.

Learn More About the DSD Diagnosis Study

Jill Jacobson, MD

jjacobson@cmh.edu • (816) 960-8803

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

Achieving Consensus on Care

The new recommendations are based on committee members’ review of existing literature and their expert opinions. They specifically address diagnosis, assessment, screening and treatment of all three hereditary polyposis syndromes in children and adolescents. With these new recommendations, gastroenterologists now have practical guidance for management of pediatric patients with these conditions.

The position papers support and educate providers to deliver informed, cautious care. Cancer risk is defined as clearly as can be, given the current evidence, and procedures and tests to prevent illness are tailored accordingly.

An Overview of the New Recommendations 

Focus on syndrome-specific targets:

• Familial adenomatous polyposis: Focus on the timing of surgery to remove the colon
• Peutz-Jeghers syndrome: Focus on avoiding polyps that cause intestinal obstruction
• Juvenile polyposis syndrome: Focus on the genetic subgroup because of differences in non-intestinal testing needs

When to perform genetic testing:

• Familial adenomatous polyposis: 12-14 years
• Peutz-Jeghers syndrome: 3 years
• Juvenile polyposis syndrome: 12-15 years

All genetic testing should be conducted in conjunction with genetic counseling.

Who to test:

• Positive family history (autosomal dominant pattern of inheritance)
• Suspicious clinical findings [bilateral retinal abnormalities CHRPE (FAP), liver cancer, hepatoblastoma (FAP)*, multiple benign desmoids (FAP), mucocutaneous freckling (PJS)]
• Meet clinical criteria (endoscopic/extraintestinal findings)

*Although these are not officially part of the recommendations, they are in clinical practice today.

Diagnostic criteria:

For the first time, consensus exists among pediatric GI specialists about how to diagnose, as shown in the table below.

Position papers: 

Complete details on the clinical recommendations for all three hereditary polyposis syndromes are included in the three ESPGHAN Polyposis Working Group position papers, available below:

• Management of Juvenile Polyposis Syndrome in Children and Adolescents¹
• Management of Peutz-Jeghers Syndrome in Children and Adolescents²
• Management of Familial Adenomatous Polyposis in Children and Adolescents³

Learn More About the Polyposis Center at Children's Mercy

Thomas M. Attard, MD

tmattard@cmh.edu • (816) 302-3028

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

References:

1. Cohen S, Hyer W, Mas E, et al. Management of Juvenile Polyposis Syndrome in Children and Adolescents: A Position Paper from the ESPGHAN Polyposis Working Group. Journal of Pediatric Gastroenterology and Nutrition. 2019;68: 453-462.

2. Latchford A, Cohen S, Auth M. et al. Management of Peutz-Jeghers Syndrome in Children and Adolescents: A Position Paper from the ESPGHAN Polyposis Working Group. Journal of Pediatric Gastroenterology and Nutrition. 2019;68:442-452.

3. Hyer W, Cohen S, Attard T, et al.Management of Familial Adenomatous Polyposis in Children and Adolescents: Position Paper from the ESPGHAN Polyposis Working Group. Journal of Pediatric Gastroenterology and Nutrition. 2019;68:428-441.

The results of their six-year effort are shown in the diagnostic criteria table below:

Complete details on the clinical recommendations for all three hereditary polyposis syndromes are included in the three ESPGHAN Polyposis Working Group position papers, available below:

• Management of Juvenile Polyposis Syndrome in Children and Adolescents
• Management of Peutz-Jeghers Syndrome in Children and Adolescents
• Management of Familial Adenomatous Polyposis in Children and Adolescents

The team was determined to keep socioeconomic status from creating barriers to access, so it still offers the option of a tablet and cell service. If a family cannot afford a smartphone, they can still participate in the program.

With the new version of the app, the registration process has been significantly streamlined. Parents can download the CHAMP App from the app store on their phone or tablet. They are given a special PIN from their CHAMP site to complete the registration process.

The updates made to the CHAMP App were made possible by funding from the Claire Giannini Fund.

Expanding the Reach of Champ

Amy Ricketts, RN-C, CHAMP Multisite Project Manager, and Lori Erickson, PhD(c), CHAMP Clinical Program Manager, have led the effort to onboard additional CHAMP sites. Today, nine sites in addition to Children’s Mercy are using the CHAMP App, and nearly 80 babies in 22 states are being actively followed. Each center cares for its own babies and contributes data to the central registry at Children’s Mercy.

Centers currently participating in CHAMP include:

• Children’s Mercy Kansas City (Missouri)
• Seattle Children’s Hospital (Washington)
• Cincinnati Children’s Hospital (Ohio)
• West Virginia University Medicine Children’s (West Virginia)
• Primary Children’s Hospital (Utah)
• Arkansas Children’s Hospital (Arkansas)
• Cook Children’s Medical Center (Texas)
• Nationwide Children’s Hospital (Ohio)
• Children’s National Hospital (Washington, D.C.)
• Texas Children’s Hospital (Texas)

To date, 490 babies have been monitored via CHAMP. The program has capacity for more sites to participate, and five are already in the process of reviewing the legal and research requirements to become part of CHAMP.

Collaborative Research is Underway

As more organizations utilize the technology, the CHAMP registry continues to expand, giving teams access to more data for research. The registry tracks an average of 660 data points and 50 videos per child. As of the end of 2019, the CHAMP registry contained 336,000 data points.

All CHAMP sites have the opportunity to submit research proposals and collaborate on projects using registry data. The following projects are in process today:

1. Parental adherence to mobile health. What are the factors that correlate to parents entering or not entering data?
2. Unplanned readmissions. Can we develop predictive analytics, based on previously entered data, to help identify future unplanned admissions and subsequently avoid them?
3. Parental experience. How can we more effectively prepare parents to care for a baby at home during the high-risk interstage period? This qualitative study involves the evaluation of 120 hours of audio interviews with parents to learn how they cope with caring for a baby with a complex condition.
4. Video scoring tool. Can we better predict risks of readmission through video scoring? Developed by Doaa Aly, MBBCH, former Ward Family Heart Center Fellow, this tool assigns a score to each video uploaded by a parent. Dr. Aly won the Outstanding Investigator Award for this tool at the Cardiology 2019 Conference at the Children’s Hospital of Philadelphia.
5. Video scoring tool, phase 2. Can we validate the findings from the video scoring tool developed by Dr. Aly? Phase 1 was conducted solely at Children’s Mercy. Phase 2 is a multisite effort to validate the original findings at all other CHAMP sites.

CHAMP is Multilingual 

If a baby comes from a non-English-speaking family, its risk of death from complications during the interstage period may be higher. To address this concern, the team developed the app in additional languages:

• Spanish
• Arabic
• Chinese
• Filipino
• French
• German
• Korean
• Vietnamese

Patient Snapshot

• 11% Nonwhite
• 16% Hispanic/Latino
• 42% live > 100 miles from care center
• 56.2% have Medicaid insurance
• 5% use non-English CHAMP app
• 50% of patients have hypoplastic left heart syndrome (HLHS) with Norwood or hybrid palliations 

​Learn More About CHAMP

Hayley Hancock, MD, CHAMP Medical Director

hshancock@cmh.edu • (816) 302-3657

Amy Ricketts, RN-C, CHAMP Multisite Project Manager

amricketts@cmh.edu • (816) 302-3657

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466 3729.