Public Health

Bella's brain scan

Born with hemimegalencephaly, Bella now has a bright future

bella's brain scans

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Bella was born with a rare condition (hemimegalencephaly) in which one half of the brain developed abnormally, causing seizures. The textbook approach is to let babies grow big enough for a dramatic surgery. But Bella’s left hemisphere was triggering so many seizures each hour that waiting would mean her life would be defined by severe disability. Children’s National Hospital is believed to be the only center in the world that calms these seizures through controlled strokes.

Procedure one occurred five days after Bella came to Children’s National Hospital from Iowa, when she was 13 days old. The team first optimized control of her seizures and obtained special magnetic resonance images to plan their approach. They glued up the branches of the left posterior cerebral artery and branches of the left middle cerebral artery. Bella had a tiny bleed that was controlled immediately in the angio suite and afterwards in the Children’s National neonatal intensive care unit.

Procedure two occurred 10 days later when Bella was 23 days old. The team waited until brain swelling had subsided and brain tissue loss had occurred from the first procedure. This time, they glued up the remaining branches of the left posterior cerebral artery and some branches of the left anterior cerebral artery.

The third and final procedure was done nine days later when Bella was 29 days old.  This time the team glued and coiled, placing little wire coils where it was unsafe to use glue, getting at the remaining small and numerous branches that remained of the left anterior cerebral artery.

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nurse checking boy's hearbeat

Children’s National launches telehealth collaboration with Whittle School & Studios

nurse checking boy's hearbeat

The School-Based Telehealth Program provides students quick access to medical care, rapid diagnosis of medical conditions, and better management of chronic conditions like asthma and diabetes, while minimizing time away from school for children – and from work for parents.

Children’s National Hospital and Whittle School & Studios announced a collaboration to provide students at the Whittle School’s D.C. campus with on-site video connectivity to health professionals at the hospital throughout the 2019-20 school year.

“We are thrilled to collaborate with Children’s National to offer our students world-class medical care from compassionate providers,” said Dennis Bisgaard, head of Whittle’s D.C. campus. “The health and safety of our students is our top priority, and this new collaboration ensures that they’ll be in excellent hands.”

A registered nurse from Children’s National will work on-site at Whittle’s D.C. campus to provide acute care, first aid, immunization record-keeping, medication management, EpiPen storage and training and more.

Children’s National’s School-Based Telehealth Program will also be available at the Whittle School. The on-site nurse will have the ability to use secure video-conferencing technology to connect students with board-certified physicians from Children’s National, if necessary.

The School-Based Telehealth Program provides students quick access to medical care, rapid diagnosis of medical conditions, and better management of chronic conditions like asthma and diabetes, while minimizing time away from school for children – and from work for parents. The program will complement existing care the student may already receive from their medical home or primary care provider.

“We are excited to collaborate with the Whittle School to design a program centered on our shared vision of helping children,” said Denice Cora-Bramble, M.D., executive vice president and chief medical officer, ambulatory and community health services at Children’s National. “Our goal is that this new collaboration will provide access to highly-specialized health care expertise to patients and families and our hope is that school-based nursing services, coupled with telehealth technology, will improve students’ health and education outcomes.”

Mihailo Kaplarevic

Extracting actionable research data faster, with fewer hassles

Mihailo Kaplarevic

Mihailo Kaplarevic, Ph.D., the newly minted Chief Research Information Officer at Children’s National Hospital and Bioinformatics Division Chief at Children’s National Research Institute, will provide computational support, advice, informational guidance, expertise in big data and data analyses for researchers and clinicians.

Kaplarevic’s new job is much like the role he played most recently at the National Heart, Lung and Blood Institute (NHLBI), assembling a team of researchers and scientists skilled in computing and statistical analyses to assist as in-house experts for other researchers and scientists.

NHLBI was the first institute within the National Institutes of Health (NIH) family to set up a scientific information office. During his tenure, a half-dozen other NIH institutions followed, setting up the same entity to help bridge the enormous gap between basic and clinical science and everything related to IT.

“There is a difference compared with traditional IT support at Children’s National – which will remain in place and still do the same sort of things they have been doing so far,” he says of The Bear Institute for Health Innovation. “The difference is this office has experience in research because every single one of us was a researcher at a certain point in our career: We are published. We applied for grants. We lived the life of a typical scientist. On top of that, we’re coming from the computational world. That helps us bridge the gaps between research and clinical worlds and IT.”

Ultimately, he aims to foster groundbreaking science by recognizing the potential to enhance research projects by bringing expertise acquired over his career and powerful computing tools to help teams achieve their goals in a less expensive and more efficient way.

“I have lived the life of a typical scientist. I know exactly how painful and frustrating it can be to want to do something quickly and efficiently but be slowed by technological barriers,” he adds.

As just one example, his office will design the high-performance computing cluster for the hospital to help teams extract more useful clinical and research data with fewer headaches.

Right now, the hospital has three independent clinical systems storing patient data; all serve a different purpose. (And there are also a couple of research information systems, also used for different purposes.) Since databases are his expertise, he will be involved in consolidating data resources, finding the best way to infuse the project with the bigger-picture mission – especially for translational science – and creating meaningful, actionable reports.

“It’s not only about running fewer queries,” he explains. “One needs to know how to design the right question. One needs to know how to design that question in a way that the systems could understand. And, once you get the data back, it’s a big set of things that you need to further filter and carefully shape. Only then will you get the essence that has clinical or scientific value. It’s a long process.”

As he was introduced during a Children’s National Research Institute faculty meeting in late-September 2019, Kaplarevic joked that his move away from pure computer science into a health care and clinical research domain was triggered by his parents: “When my mom would introduce me, she would say ‘My son is a doctor, but not the kind of doctor who helps other people.’ ”

Some of that know-how will play out by applying tools and methodology to analyze big data to pluck out the wheat (useful data) from the chaff in an efficient and useful way. On projects that involve leveraging cloud computing for storing massive amounts of data, it could entail analyzing the data wisely to reduce its size when it comes back from the cloud – when the real storage costs come in. “You can save a lot of money by being smart about how you analyze data,” he says.

While he expects his first few months will be spent getting the lay of the land, understanding research project portfolios, key principal investigators and the pediatric hospital’s biggest users in the computational domain, he has ambitious longer-term goals.

“Three years from now, I would like this institution to say that the researchers are feeling confident that their research is not affected by limitations related to computer science in general. I would like this place to become a very attractive environment for up-and-coming researchers as well as for established researchers because we are offering cutting-edge technological efficiencies; we are following the trends; we are a secure place; and we foster science in the best possible way by making computational services accessible, affordable and reliable.”

Lee Beers

Getting to know Lee Beers, M.D., FAAP, future president-elect of AAP

Lee Beers

Lee Savio Beers, M.D., FAAP, Medical Director of Community Health and Advocacy at the Child Health Advocacy Institute (CHAI) at Children’s National Hospital carved out a Monday morning in late-September 2019, as she knew the American Academy of Pediatrics (AAP) would announce the results of its presidential election, first by telephone call, then by an email to all of its members.  Her husband blocked off the morning as well to wait with her for the results.  She soon got the call that she was elected by her peers to become AAP president-elect, beginning Jan. 1, 2020. Dr. Beers will then serve as AAP president in 2021 for a one-year term.

That day swept by in a rush, and then the next day she was back in clinic, caring for her patients, some of them teenagers whom she had taken care of since birth. Seeing children and families she had known for such a long time, some of whom had complex medical needs, was a perfect reminder of what originally motivated Dr. Beers to be considered as a candidate in the election.

“When we all work together – with our colleagues, other professionals, communities and families – we can make a real difference in the lives of children.  So many people have reached out to share their congratulations, and offer their support or help. There is a real sense of collaboration and commitment to child health,” Dr. Beers says.

That sense of excitement ripples through Children’s National.

“Dr. Beers has devoted her career to helping children. She has developed a national advocacy platform for children. I can think of no better selection for the president-elect role of the AAP. She will be of tremendous service to children within AAP national leadership,” says Kurt Newman, M.D., Children’s National Hospital President and CEO.

AAP comprises 67​,000 pediatricians, and its mission is to promote and safeguard the health and well-being of all children – from infancy to adulthood.

The daughter of a nuclear engineer and a schoolteacher, Dr. Beers knew by age 5 that she would become a doctor. Trained as a chemist, she entered the Emory University School of Medicine after graduation. After completing residency at the Naval Medical Center, she became the only pediatrician assigned to the Guantanamo Bay Naval Station.

That assignment to Cuba, occurring so early in her career, turned out to be a defining moment that shapes how she partners with families and other members of the team to provide comprehensive care.

“I was a brand-new physician, straight out of residency, and was the only pediatrician there so I was responsible for the health of all of the kids on the base. I didn’t know it would be this way at the time, but it was formative. It taught me to take a comprehensive public health approach to taking care of kids and their families,” she recalls.

On the isolated base, where she also ran the immunization clinic and the nursery, she quickly learned she had to judiciously use resources and work together as a team.

“It meant that I had to learn how to lead a multi-disciplinary team and think about how our health care systems support or get in the way of good care,” she says.

One common thread that unites her past and present is helping families build resiliency to shrug off adversity and stress.

“The base was a difficult and isolated place for some families and individuals, so I thought a lot about how to support them. One way is finding strong relationships where you are, which was important for patients and families miles away from their support systems. Another way is to find things you could do that were meaningful to you.”

Cuba sits where the Atlantic Ocean, Caribbean Sea and Gulf of Mexico meet. Dr. Beers learned how to scuba dive there – something she never would have done otherwise – finding it restful and restorative to appreciate the underwater beauty.

“I do think these lessons about resilience are universal. There are actually a lot of similarities between the families I take care of now, many of whom are in socioeconomically vulnerable situations, and military families when you think about the level of stress they are exposed to,” she adds.

Back stateside in 2001, Dr. Beers worked as a staff pediatrician at the National Naval Medical Center in Bethesda, Maryland, and Walter Reed Army Medical Center in Washington, D.C. In 2003, Dr. Beers joined Children’s National Hospital as a general pediatrician in the Goldberg Center for Community Pediatric Health. Currently, she oversees the DC Collaborative for Mental Health in Pediatric Primary Care, a public-private coalition that elevates the standards of mental health care for all children, and is Co-Director of the Early Childhood Innovation Network. She received the Academic Pediatric Association’s 2019 Public Policy and Advocacy Award.

As a candidate, Dr. Beers pledged to continue AAP’s advocacy and public policy efforts and to further enhance membership diversity and inclusion. Among her signature issues:

  • Partnering with patients, families, communities, mental health providers and pediatricians to co-design systems to bolster children’s resiliency and to alleviate growing pediatric mental health concerns
  • Tackling physician burnout by supporting pediatricians through office-based education and systems reforms
  • Expanding community-based prevention and treatment

“I am humbled and honored to have the support of my peers in taking on this newest leadership role,” says Dr. Beers. “AAP has been a part of my life since I first became a pediatrician, and my many leadership roles in the DC chapter and national AAP have given me a glimpse of the collective good that pediatricians can accomplish by working together toward common strategic goals.”

AAP isn’t just an integral part of her life, it’s where she met her future husband, Nathaniel Beers, M.D., MPA, FAAP, President of The HSC Health Care System. The couple’s children regularly attended AAP meetings with them when they were young.

Just take a glimpse at Lee Beers’ Twitter news feed. There’s a steady stream of images of her jogging before AAP meetings to amazing sunrises, jogging after AAP meetings to stellar sunsets and always, always, images of the entire family, once collectively costumed as The Incredibles.

“I really do believe that we have to set an example: If we are talking about supporting children and families in our work, we have to set that example in our own lives. That looks different for everyone, but as pediatricians and health professionals, we can model prioritizing our families while still being committed to our work,” she explains.

“Being together in the midst of the craziness is just part of what we do as a family. We travel a lot, and our kids have gone with us to AAP meetings since they were infants. My husband even brought our infant son to a meeting at the mayor’s office when he was on paternity leave. Recognizing that not everyone is in a position to be able to do things like that, it’s important for us to do it – to continue to change the conversation and make it normal to have your family to be part of your whole life, not have a separate work life and a separate family life.”

Tania Ahluwalia

Simulation curriculum for emergency medicine trainees in India

Tania Ahluwalia

“It is essential to equip emergency physicians in India with these necessary skills so they can provide the best acute care for children and help the country overcome its burden of pediatric illness. This project focuses on simulation training because it is a very effective way to practice clinical and communication skills,” says Tania Ahluwalia, M.D., FAAP.

India has a high burden of pediatric illness, and close to 1 million children die each year.

Despite those staggering public health challenges, pediatric emergency medicine training remains in its infancy in India. Tania Ahluwalia, M.D., FAAP, associate director of Global Health Programs, Division of Emergency Medicine and Trauma Services at Children’s National Hospital has been working with the Ronald Reagan Institute of Emergency Medicine to help address that training gap.

“It is essential to equip emergency physicians in India with these necessary skills so they can provide the best acute care for children and help the country overcome its burden of pediatric illness. This project focuses on simulation training because it is a very effective way to practice clinical and communication skills,” Dr. Ahluwalia says.

Each October a team led by Dr. Ahluwalia teaches Pediatric Emergency Medicine modules in India based on a three-year curriculum.  In October 2019, they will focus on neonatology. And thanks to a 2019-2020 Global Health Initiative Exploration in Global Health Award presented during Research and Education Week at Children’s National, over two weeks Dr. Ahluwalia will visit various cities in India with a team that includes:

  • Kaitlyn Boggs, M.D., a second-year pediatric resident at Children’s National
  • Camilo Gutierrez, M.D., Children’s National Emergency Medicine and Trauma Services
  • Simone Lawson, M.D., Children’s National Emergency Medicine and Trauma Services
  • Shobhit Jain, Kansas City
  • Shiva Kalidindi, Nemours Children’s Hospital
  • Manu Madhok, Minneapolis

For the study, about 80 trainees participating in postgraduate emergency medicine training programs in India will practice skills, such as intubating a patient, using the same medical equipment and mannequins of the same size as pediatric patients. The trainees will review several pediatric emergency medicine cases that were developed based on a needs assessment at partner programs in India. First, visiting faculty members will watch videos developed by Dr. Ahluwalia, Michael Hrdy, M.D., and Rachael Batabyal, M.D., and will review literature on how to conduct simulation in a developing country.

Faculty teaching neonatology, use of simulation modules and other pediatric emergency medicine training topics will visit Bangalore, Bhubaneswar, Dehradun, Delhi, Kochi, Kolkata, Kozhikhode, Madurai and Mumbai. (Kate Douglass, M.D., of the George Washington University and Serkan Toy, Ph.D., an educational psychologist at John Hopkins University, have been heavily involved in this project but will not travel to India in October.)

“My passion is global education so, for me, this project will be a success if we improve the trainees’ comfort, knowledge and skill at providing patient care after undergoing this simulation-based curriculum. We also want to improve our faculty’s capacity to teach through these simulation modules, so there are definitely learning opportunities for both U.S. teachers and Indian trainees,” she adds.

Financial support for research described in this post was provided by the 2019-2020 Global Health Initiative Exploration in Global Health Award.

gut bacteria

Understanding gut bacteria: forces for good (and sometimes evil)

gut bacteria

In a paper published Sept. 11, 2019, in PLOS ONE, a multi-institutional research team led by George Washington University (GW) faculty found 157 different types of organisms (eight phyla, 18 classes, 23 orders, 38 families, 59 genera and 109 species) living inside the guts of healthy volunteers.

Back in 2015, an interdisciplinary group of research scientists made their case during a business pitch competition: They want to create a subscription-based service, much like 23andMe, through which people could send in samples for detailed analyses. The researchers would crunch that big data fast, using a speedy algorithm, and would send the consumer a detailed report.

But rather than ancestry testing via cheek swab, the team sought to determine the plethora of diverse bacterial species that reside inside an individual’s gut in their ultimate aim to improve public health.

Hiroki Morizono, Ph.D., a member of that team, contributed detailed knowledge of Bacteroides, a key organism amid the diverse array of bacterial species that co-exist with humans, living inside our guts. These symbiotic bacteria convert the food we eat into elements that ensure their well-being as well as ours.

“Trillions of bacteria live in the gut. Bacteroides is one of the major bacterial species,” says Morizono, a principal investigator in the Center for Genetic Medicine Research at Children’s National in Washington, D.C. “In our guts they are usually good citizens. But if they enter our bloodstream, they turn evil; they’re in the wrong place. If you have a bacteroides infection, the mortality rate is 19%, and they resist most antibiotic treatments.”

The starting point for their project – as well as step one for better characterizing the relationship between gut bacteria and human disease – is taking an accurate census count of bacteria residing there.

In a paper published Sept. 11, 2019, in PLOS ONE, a multi-institutional research team led by George Washington University (GW) faculty did just that, finding 157 different types of organisms (eight phyla, 18 classes, 23 orders, 38 families, 59 genera and 109 species) living inside the guts of healthy volunteers.

The study participants were recruited through flyers on the GW Foggy Bottom campus and via emails.  They jotted down what they ate and drank daily, including the brand, type and portion size. They complemented that food journal by providing fecal samples from which DNA was extracted. Fifty fecal metagenomics samples randomly selected from the Human Microbiome Project Phase I research were used for comparison purposes.

“The gut microbiome inherently is really, really cool. In the process of gathering this data, we are building a knowledge base. In this paper, we’re saying that by looking at healthy people, we should be able to establish a baseline about what a normal, healthy gut microbiome should look like and how things may change under different conditions,” Morizono adds.

And they picked a really, really cool name for their bacteria abundance profile: GutFeelingKB.

“KB is knowledge base. Our idea, it’s a gut feeling. It’s a bad joke,” he admits. “Drosophila researchers have the best names for their genes. No other biology group can compete. We, at least, tried.”

Next, the team will continue to collect samples to build out their bacteria baseline, associate it with clinical data, and then will start looking at the health implications for patients.

“One thing we could use this for is to understand how the bacterial population in the gut changes after antibiotic treatment. It’s like watching a forest regrow after a massive fire,” he says. “With probiotics, can we do things to encourage the right bacteria to grow?”

In addition to Morizono, study co-authors include Lead Author Charles H. King, and co-authors Hiral Desai, Allison C. Sylvetsky, Jonathan LoTempio, Shant Ayanyan, Jill Carrie, Keith A. Crandall, Brian C. Fochtman, Lusine Gasparyan, Naila Gulzar, Najy Issa, Lopa Mishra, Shuyun Rao, Yao Ren, Vahan Simonyan, Krista Smith and Senior Author, Raja Mazumder, all of George Washington University; Paul Howell and Sharanjit VedBrat, of KamTek Inc.; Konstantinos Krampis, of City University of New York; Joseph R. Pisegna, of VA Greater Los Angeles Healthcare System; and Michael D. Yao, of Washington DC VA Medical Center.

Financial support for research described in this post was provided by the National Science Foundation under award number 1546491 and the National Institutes of Health National Center for Advancing Translational Sciences under award number UL1TR000075.

rabies virus illustration

Critters bugging! Test your infectious disease knowledge


Dengue virus

Children’s National/NIH team competes in #IDbugbowl

Dengue virus

IDBugBowl team member Maria Susana Rueda-Altez, M.D., hopes her knowledge of infectious diseases common to Peru, like dengue virus, will give her team an advantage.

It’s a bird. It’s a plane. No, it’s an infectious agent that zipped past country borders, infecting international passengers who shared the same commercial aircraft as a person who had symptomatic illness.

The buzzer rings. And the correct answer is: What is severe acute respiratory syndrome?

This fall, a combined team from Children’s National in Washington, D.C. and the National Institutes of Health (NIH) will compete against three other teams testing their collective infectious disease knowledge through IDBugBowl, a Jeopardy-style quiz geared toward fellows, residents and medical students. The competition is held during IDWeek2019. “From anaplasmosis to Zika, any topic is fair game,” according to organizers.

“BugBowl has become so popular that the IDWeek 2019 program committee carved out a separate time for the contest to ensure it would not conflict with any other symposia,” says Roberta L. DeBiasi, M.D., MS, chief of the Division of Pediatric Infectious Diseases at Children’s National. “On a day-to-day basis, we all contend with serious infectious diseases that have the potential to jeopardize human health. However, this event helps to expand knowledge among the general public in a fun and engaging way.”

The Children’s National/NIH team participating in the Oct. 5 trivia contest includes:

  • Kevin Lloyd, M.D., third-year pediatrics resident
  • Maria Susana Rueda-Altez, M.D., third-year pediatrics resident
  • Kanal Singh, M.D., fellow, adult infectious diseases at the National Institutes of Health (NIH) and
  • Alexandra Yonts, M.D., fellow, pediatric infectious diseases at Children’s National

Even though she has little formal training in infectious diseases, team member Dr. Rueda-Altez says: “One thing I have in my favor is that I’m from Peru. We’re used to seeing infectious diseases that are less common elsewhere, including tuberculosis and hantavirus.”

And while disease-carrying mosquitoes aren’t abundant at Peru’s higher altitudes, closer to sea level and in its rain forests, infected mosquitoes spread chikungunya, dengue, malaria and Zika, she adds.

Take this quiz to test your infectious disease knowledge.

tube labeled "CRISPR"

$2M from NIH to extract meaningful data from CRISPR screens

tube labeled "CRISPR"

Protein-coding genes comprise a mere 1% of DNA. While the other 99% of DNA was once derided as “junk,” it has become increasingly apparent that some non-coding genes enable essential cellular functions.

Wei Li, Ph.D., a principal investigator in the Center for Genetic Medicine Research at Children’s National in Washington, D.C., proposes to develop statistical and computational methods that sidestep existing hurdles that currently complicate genome-wide CRISPR/Cas9 screening. The National Institutes of Health has granted him $2.23 million in funding over five years to facilitate the systematic study of genes, non-coding elements and genetic interactions in various biological systems and disease types.

Right now, a large volume of screening data resides in the public domain, however it is difficult to compare data that is stored in one library with data stored at a different library. Over the course of the five-year project, Li aims to:

  • Improve functional gene identification from CRISPR screens.
  • Develop new analyses algorithms for screens targeting non-coding elements.
  • Study genetic interactions from CRISPR screens targeting gene pairs.

Ultimately, Li’s work will examine a range of disease types. Take cancer.

“There is abundant information already available in the public domain, like the Project Achilles  from the Broad Institute. However, no one is looking to see what is going in inside these tumors,” Li says. “Cancer is a disease of uncontrolled cell growth that makes tumors grow faster.”

Li and colleagues are going to ask which genes control this process by looking at genes that hit the brakes on cell growth as well as genes that pump the gas.

“You knock out one gene and then look: Does the cell grow faster or does it grow more slowly? If the cell grows more slowly, you know you are knocking out a gene that has the potential to stop tumor growth. If cells are growing faster, you know that you’re hitting genes that suppress cancer cell growth.”

In a nutshell, CRISPR (clustered regularly interspaced short palindromic repeats) screens knock out different genes and monitor changes in corresponding cell populations. When CRISPR first became popular, Li decided he wanted to do something with the technology. So, as a Postdoc at Harvard, he developed comprehensive computational algorithms for functional screens using CRISPR/Cas9.

To reach as many people as possible, he offered that MAGeCK/MAGeCK-VISPR software free to as many researchers as possible, providing source code and offering internet tutorials.

“So far, I think there are quite a lot of people using this. There have been more than 40,000 software downloads,” he adds. “It’s really exciting and revolutionary technology and, eventually, we hope the outcomes also will be exciting. We hope to find something really helpful for cancer patients.”

Research reported in this publication was supported by the National Human Genome Research Institute of the National Institutes of Health under award number R01HG010753.

little boy using asthma inhaler

Searching for the molecular underpinnings of asthma exacerbations

little boy using asthma inhaler

It’s long been known that colds, flu and other respiratory illnesses are major triggers for asthma exacerbations, says asthma expert Stephen J. Teach, M.D., MPH. Consequently, a significant body of research has focused on trying to figure out what’s happening on the cellular or molecular level as these illnesses progress to exacerbations.

People with asthma can be indistinguishable from people who don’t have this chronic airway disease – until they have an asthma attack, also known as an exacerbation. During these events, their airways become inflamed and swollen and produce an abundance of mucus, causing dangerous narrowing of the bronchial tubes that leads to coughing, wheezing and trouble breathing. These events are a major cause of morbidity and mortality, leading to the deaths of 10 U.S. residents every day, according to the Centers for Disease Control and Prevention.

It’s long been known that colds, flu and other respiratory illnesses are major triggers for asthma exacerbations, says Children’s National in Washington, D.C., asthma expert Stephen J. Teach, M.D., MPH. Consequently, a significant body of research has focused on trying to figure out what’s happening on the cellular or molecular level as these illnesses progress to exacerbations. Targeted searches have identified several different molecular pathways that appear to be key players in this phenomenon. However, Dr. Teach says researchers have been missing a complete and unbiased snapshot of all the important pathways in illness-triggered exacerbations and how they interrelate.

To develop this big picture view, Dr. Teach and  Inner-City Asthma Consortium colleagues recruited 208 children ages 6-17 years old with severe asthma – marked by the need for daily doses of inhaled corticosteroids, two hospitalizations or systemic corticosteroid treatments over the past year, and a high concentration of asthma-associated immune cells – from nine pediatric medical centers across the country, including Children’s National. (Inhaled corticosteroids are a class of medicine that calms inflamed airways.) The researchers collected samples of nasal secretions and blood from these patients at baseline, when all of them were healthy.

Then, they waited for these children to show symptoms of respiratory illnesses. Within six days of cold symptoms, the researchers took two more samples of nasal secretions and blood. They also administered breathing tests to determine whether these respiratory illnesses led to asthma exacerbations and recorded whether these patients were treated with systemic corticosteroids to stem the associated respiratory inflammation.

The researchers examined nasal fluid samples for evidence of viral infection during illness and used analytical methods to identify the causative virus. They analyzed all the samples they collected for changes in concentrations of various immune cells. They also looked globally in these samples for changes in gene expression compared with baseline and between the two collection periods during respiratory illness.

Together, this information told the molecular story about what took place after these children got sick and after some of them developed exacerbations. Of the 208 patients recruited, 106 got respiratory illnesses during the six-month study period, leading to a total of 154 illness events. Of those, 47 caused exacerbations, and 107 didn’t.

About half the exacerbations appeared to have been triggered by a rhinovirus, a cause of common colds, the research team reports in a study published online April 8, 2019, in Nature Immunology. The other children’s cold-like symptoms could have been triggered by pollution, allergens or other irritants.

In most exacerbations, virally triggered or not, the researchers saw early activation of a network of genes that appeared to be associated with SMAD3, a signaling molecule already known to be involved in airway inflammation. At the same time, genes that control a set of immune cells known as lymphocytes were turned down. However, as the exacerbation progressed and worsened, the researchers saw gene networks turned on that related to airway narrowing, mucus hypersecretion and activation of other immune cells.

Exacerbations triggered by viruses were associated with multiple inflammatory pathways, in contrast to those in which viruses weren’t found, which were associated with molecular pathways that affected cells in the airway lining.

The researchers validated these findings in 19 patients who each got respiratory illnesses at least twice during the study period but only developed an exacerbation during one of these episodes, finding the same upregulated and downregulated molecular pathways in these patients as in the study population as a whole. They also identified a set of molecular risk factors in patients at baseline – signatures of gene activation that appeared to put patients at risk for exacerbations when they got sick. When patients were treated with systemic corticosteroids during exacerbations, these medicines appeared to restore only some of the affected molecular pathways to normal, healthy levels. Other molecular pathways remained markedly changed.

Each finding could represent a new target for drugs that could prevent or more effectively treat exacerbations, keeping more patients with asthma healthy and out of the hospital.

“Our consortium study found increased gene expression of enzymes that produce molecules that contribute to narrowed airways and dilated blood vessels,” Dr. Teach adds. “This is especially intriguing because drugs that target kallikreins or bradykinin may help treat asthma attacks that aren’t caused by viruses.”

In addition to Dr. Teach, study co-authors include Lead Author Matthew C. Altman, University of Washington; Michelle A. Gill, Baomei Shao and Rebecca S. Gruchalla, all of University of Texas Southwestern Medical Center; Elizabeth Whalen and Scott Presnell of Benaroya Research Institute; Denise C. Babineau and Brett Jepson of Rho, Inc.; Andrew H. Liu, Children’s Hospital Colorado; George T. O’Connor, Boston University School of Medicine; Jacqueline A. Pongracic, Ann Robert H. Lurie Children’s Hospital of Chicago; Carolyn M. Kercsmar and Gurjit K. Khurana Hershey, , Cincinnati Children’s Hospital; Edward M. Zoratti and Christine C. Johnson, Henry Ford Health System; Meyer Kattan, Columbia University College of Physicians and Surgeons; Leonard B. Bacharier and Avraham Beigelman, Washington University, St. Louis; Steve M. Sigelman, Peter J. Gergen, Lisa M. Wheatley and Alkis Togias, National Institute of Allergy and Infectious Diseases; and James E. Gern, William W. Busse and Senior author Daniel J. Jackson, University of Wisconsin School of Medicine and Public Health.

Funding for research described in this post was provided by the National Institute of Allergy and Infectious Diseases under award numbers 1UM1AI114271 and UM2AI117870; CTSA under award numbers UL1TR000150, UL1TR001422 and 5UL1TR001425; the National Institutes of Health under award number UL1TR000451;  CTSI under award number 1UL1TR001430; CCTSI under award numbers UL1TR001082 and 5UM1AI114271; and NCATS under award numbers UL1 TR001876 and UL1TR002345.

Epstein Barr virus

Fighting lymphoma with targeted T-cells

Epstein-Barr virus

The Epstein-Barr virus (EBV) is best known as the cause of mononucleosis, the ubiquitous “kissing disease” that most people contract at some point in their life. But in rare instances, this virus plays a more sinister role as the impetus of lymphomas, cancers that affect the white blood cells known as lymphocytes.

The Epstein-Barr virus (EBV) is best known as the cause of mononucleosis, the ubiquitous “kissing disease” that most people contract at some point in their life. But in rare instances, this virus plays a more sinister role as the impetus of lymphomas, cancers that affect the white blood cells known as lymphocytes. EBV-associated lymphomas account for about 40% of Hodgkin lymphomas, 20% of diffuse large B-cell lymphomas, and more than 90% of natural killer/T-cell lymphomas. This latter type of lymphoma typically has a very poor prognosis even with the “standard of care” lymphoma treatments such as chemotherapy and/or radiation.

When these interventions fail, the only curative approach is an allogeneic  hematopoietic stem cell transplant from a healthy donor, a treatment that’s tough on patients’ bodies and carries significant risks, says Lauren P. McLaughlin, M.D., a pediatrician specializing in hematology and oncology at Children’s National in Washington, D.C. Patients who receive these allogenic transplants are immune-compromised until the donor cells engraft; the grafts can attack patients’ healthy cells in a phenomenon called graft versus host disease; and if patients relapse or don’t respond to this treatment, few options remain.

To help improve outcomes, Dr. McLaughlin and colleagues tested an addition to the allogeneic hematopoietic stem cell transplant procedure for patients with EBV-associated lymphomas: infusion of a type of immune cell called T cells specifically trained to fight cells infected with EBV.

Dr. McLaughlin, along with Senior Author Catherine M. Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research and the Program for Cell Enhancement and Technologies for Immunotherapy at Children’s National, and colleagues tested this therapy in 26 patients treated at Children’s National or Baylor College of Medicine. They published these results online on Sept. 27, 2018, in the journal Blood. The study was a Phase I clinical trial, meaning that the therapy was tested primarily for safety, with efficacy as a secondary aim.

Seven patients who received the therapy had active disease that had not responded to conventional therapies. The other 19 were patients deemed to be at high risk for relapse.

Before each patient received their stem cell transplant, their donors gave an additional blood sample to generate the cancer-fighting T cells. Over the next 8 to 10 weeks, the researchers painstakingly manufactured the immune cells known as T-cells that specifically targeted EBV, growing these cells into numbers large enough for clinical use. Then, as early as 30 days after transplant, the researchers infused these T-cells into patients administering at least two doses, spaced two weeks apart.

Over the next several weeks, the researchers at CNMC and Baylor College of Medicine monitored patients with comprehensive exams to see how they fared after these transplants. The results showed that adverse effects from the treatment were exceedingly rare. There were no immediate infusion-related toxicities to the T-cell therapy and only one incident of dose-limiting toxicity.

This therapy may be efficacious, depending on the individual patients’ circumstances, Dr McLaughlin adds. For those in complete remission but at high risk of relapsing, the two-year survival rate was 78%, suggesting that the administration of this novel T-cell therapy may give the immune system a boost to prevent the lymphoma from returning after transplant. For patients with active T-cell lymphomas, two-year survival rates were 60%. However, even these lower rates are better than the historical norm of 30-50%, suggesting that the targeted T-cell therapies could help fight disease in patients with this poor prognosis lymphoma.

Dr. McLaughlin, the study’s lead author and a Lymphoma Research Foundation grantee, notes that researchers have more work to do before this treatment becomes mainstream. For example, this treatment will need to be tested in larger populations of patients with EBV-related lymphoma to determine who would derive the most benefit, the ideal dose and dose timing. It also may be possible to extend targeted T-cell treatments like this to other types of cancers. In the future, Dr. McLaughlin adds, it may be possible to develop T-cells that could be used “off the shelf”—in other words, they wouldn’t need to come from a matched donor and would be ready to use whenever a recipient needs them. Another future goal is using this therapy as one of the first lines of treatment rather than as a last resort.

“Our ultimate goal is to find a way to avoid chemotherapy and/or radiation therapy while still effectively treating a patient’s cancer,” she says. “Can you use the immune system to do that job? We’re working to answer that question.”

In addition to Drs. McLaughlin and Bollard, study co-authors include Rayne Rouce, Stephen Gottschalk, Vicky Torrano, George Carrum, Andrea M. Marcogliese, Bambi Grilley, Adrian P. Gee, Malcolm K. Brenner, Cliona M. Rooney and Helen E. Heslop, all of Baylor College of Medicine; Meng-Fen Wu from the Dan L. Duncan Comprehensive Cancer Center; and Fahmida Hoq and Patrick J. Hanley, Ph.D. from Children’s National in Washington, D.C.

mannequins in a sled

Training teams for timely NICU evacuation

mannequins in a sled

From June 2015 to August 2017, 213 members of NICU staff took part in simulated drills, honing their skills by practicing with mannequins with varying levels of acuity.

In late August 2011, a magnitude 5.8 earthquake – the strongest east of the Mississippi since 1944 – shook Washington, D.C., with such force that it cracked the Washington Monument and damaged the National Cathedral.

On the sixth floor of the neonatal intensive care unit (NICU) at Children’s National in Washington, D.C., staff felt the hospital swaying from side to side.

After the shaking stopped, they found the natural disaster exposed another fault: The unit’s 200-plus staff members were not all equally knowledgeable or confident regarding the unit’s plan for evacuating its 66 newborns or their own specific role during an emergency evacuation.

More than 900 very sick children are transferred to Children’s National NICU from across the region each year, and a high percentage rely on machines to do the work that their tiny lungs and hearts are not yet strong enough to do on their own.

Transporting fragile babies down six flights of stairs along with vital equipment that keeps them alive requires planning, teamwork and training.  

“Fires, tornadoes and other natural disasters are outside of our team’s control. But it is within our team’s control to train NICU staff to master this necessary skill,” says Lisa Zell, BSN, a clinical educator. Zell is also lead author of a Children’s National article featured on the cover of the July/September 2019 edition of The Journal of Perinatal & Neonatal Nursing. “Emergency evacuations trigger safety concerns for patients as well as our own staff. A robust preparedness plan that is continually improved can alleviate such fears,” Zell adds.

Children’s National is the nation’s No. 1 NICU, and its educators worked with a diverse group within Children’s National to design and implement periodic evacuation simulations. From June 2015 to August 2017, 213 members of NICU staff took part in simulated drills, honing their skills by practicing with mannequins with varying levels of acuity.

“Each simulation has three objectives. First, the trainee needs to demonstrate knowledge of their own individual role in an evacuation. Second, they need to know the evacuation plan so well they can explain it to someone else. And finally, they need to demonstrate that if they had to evacuate the NICU that day, they could do it safely,” says Lamia Soghier, M.D., FAAP, CHSE, NICU medical director and the study’s senior author.

The two-hour evacuation simulation training at Children’s National begins with a group prebrief. During this meeting, NICU educators discuss the overarching evacuation plan, outline individual roles and give a hands-on demonstration of all of the evacuation equipment.

This equipment includes emergency backpacks, a drip calculation sheet and an emergency phrase card. Emergency supply backpacks are filled with everything that each patient needs post evacuation, from suction catheters, butterfly needles and suture removal kits to flashlights with batteries.

Each room is equipped with that emergency backpack which is secured in a locked cabinet. Every nurse has a key to access the cabinet at any time.

Vertical evacuation scenarios are designed to give trainees a real-world experience. Mannequins that are intubated are evacuated by tray, allowing the nurse to provide continuous oxygen with the use of a resuscitation bag during the evacuation. Evacuation by sled allows three patients to be transported simultaneously. Patients with uncomplicated conditions can be lifted out of their cribs and swiftly carried to safety.

Teams also learn how to calm the nerves of frazzled parents and enlist their help. “Whatever we need to do, we will to get these babies out alive,” Joan Paribello, a clinical educator, tells 15 staff assembled for a recent prebriefing session.

An “X” on the door designates rooms already evacuated. A designated charge nurse and another member of the medical team remain in the unit until the final patient is evacuated to make a final sweep.

The simulated training ends with a debrief session during which issues that arose during the evacuation are identified and corrected prior to subsequent simulated trainings, improving the safety and expediency of the exercise.

Indeed, as Children’s National NICU staff mastered these evacuation simulations, evacuation times dropped from 21 minutes to as little as 16 minutes. Equally important, post evacuation surveys indicate:

  • 86% of staff report being more comfortable in being able to safely evacuate the Children’s National NICU
  • 94% of NICU staff understand the overall evacuation plan and
  • 97% of NICU staff know their individual role during an evacuation.

“One of the most surprising revelations regarded one of the most basic functions in any NICU,” Dr. Soghier adds. “Once intravenous tubing is removed from its pump, the rate at which infusions drip needs to be calculated manually. We created laminated cards with pre-calculated drip rates to enable life-saving fluid delivery to continue without interruption.”

In addition to Zell and Dr. Soghier, study co-authors include Carmen Blake, BSN; Dawn Brittingham, MSN; and Ann-Marie Brown, MSN.

Test tube with DNA

“Liquid biopsies” could track diffuse midline gliomas

Test tube with DNA

A multi-institutional team led by researchers at Children’s National in Washington, D.C., developed and tested “liquid biopsy,” a measure of circulating tumor DNA in patients’ cerebrospinal fluid and blood plasma. They show that quantifying the amount of circulating tumor DNA possessing key mutations characteristic of diffuse midline gliomas could reliably predict the tumors’ response to radiotherapy.

Diffuse midline gliomas are rare, diagnosed in fewer than 800 Americans every year, the majority of whom are children. These cancers arise in the cellular “glue” that holds the brain and spinal cord’s neurons together, grow swiftly and have no cure. About half of patients with these cancers, including diffuse intrinsic pontine glioma, die within one year of diagnosis.

Clinical trials are increasingly investigating new treatments that could offer hope for patients and their families. Yet, thus far, there have been few ways to track the progression of these conditions, offering little insight on whether a treatment is hitting its intended goal.

To solve this problem, a multi-institutional team led by researchers at Children’s National in Washington, D.C., developed and tested “liquid biopsy,” a measure of circulating tumor DNA in patients’ cerebrospinal fluid and blood plasma. They show that quantifying the amount of circulating tumor DNA possessing key mutations characteristic of these cancers could reliably predict the tumors’ response to radiotherapy. The scientists published their results online Oct. 15, 2018, in Clinical Cancer Research.

“We heard from our clinician colleagues that many kids were coming in and their magnetic resonance imaging (MRI) suggested a particular type of tumor. But it was always problematic to identify the tumor’s molecular subtype,” says Javad Nazarian, Ph.D., MSC, a principal investigator in Children’s Center for Genetic Medicine Research. “Our colleagues wanted a more accurate measure than MRI to find the molecular subtype. That raised the question of whether we could actually look at their blood to determine the tumor subtype.”

Children’s liquid biopsy, which remains at the research phase, starts with a simple blood draw using the same type of needle as is used when people donate blood. When patients with brain tumors provide blood for other laboratory testing, a portion of it is used for the DNA detective work. Just as a criminal leaves behind fingerprints, tumors shed telltale clues in the blood. The team at Children’s National searches for the histone 3K27M (H3K27M), a mutation associated with worse clinical outcomes.

“With liquid biopsy, we were able to detect a few copies of tumor DNA that were hiding behind a million copies of healthy DNA,” Nazarian says. “The blood draw and liquid biopsy complement the MRI. The MRI gives the brain tumor’s ZIP code. Liquid biopsy gives you the demographics within that ZIP code.”

Working with collaborators around the nation, Children’s National continues to refine the technology to improve its accuracy.

Even though this research technique is in its infancy, the rapid, cheap and sensitive technology already is being used by people around the globe.

“People around the world are sending blood to us, looking for this particular mutation, H3K27M,” says Lindsay B. Kilburn, M.D., a neuro–oncologist, principal investigator at Children’s National for the Pacific Pediatric Neuro-Oncology Consortium, and study co-author. “In many countries or centers children to not have access to teams experienced in taking a biopsy of tumors in the brainstem, they can perform a simple blood draw and have that blood processed and analyzed by us. In only a few days, we can provide important molecular information on the tumor subtype previously only available to patients who had undergone a tumor biopsy.”

With that DNA finding, physicians can make more educated therapeutic decisions, including prescribing medications that could not have been given previously, Nazarian adds.

In addition to Nazarian and Dr. Kilburn, study co-authors include Eshini Panditharatna, Madhuri Kambhampati, Heather Gordish-Dressman, Ph.D., Suresh N. Magge, M.D., John S. Myseros, M.D., Eugene I. Hwang, M.D., and Roger J. Packer, M.D., all of Children’s National; Mariam S. Aboian, Nalin Gupta, Soonmee Cha, Michael Prados and Co-Senior Author Sabine Mueller, all of University of California, San Francisco; Cassie Kline, UCSF Benioff Children’s Hospital;  John R. Crawford, UC San Diego; Katherine E. Warren, National Cancer Institute; Winnie S. Liang and Michael E. Berens, Translational Genomics Research Institute; and Adam C. Resnick, Children’s Hospital of Philadelphia.

Financial support for the research described in the report was provided by the V Foundation for Cancer Research, Goldwin Foundation, Pediatric Brain Tumor Foundation, Smashing Walnuts Foundation, The Gabriella Miller Kids First Data Resource Center, Zickler Family Foundation, Clinical and Translational Science Institute at Children’s National under award 5UL1TR001876-03, Piedmont Community Foundation, Musella Foundation for Brain Tumor Research, Mathew Larson Foundation, The Lilabean Foundation for Pediatric Brain Cancer Research, The Childhood Brain Tumor Foundation, the National Institutes of Health and American Society of Neuroradiology.

Cholesterol plaque in artery

Looking for atherosclerosis’ root cause

Cholesterol plaque in artery

A multi-institutional team led by research faculty at Children’s National in Washington, D.C., finds that extracellular vesicles derived from kids’ fat can play a pivotal role in ratcheting up risk for atherosclerotic cardiovascular disease well before any worrisome symptoms become visible.

According to the Centers for Disease Control and Prevention, about one in five U.S. kids aged 6 to 19 is obese, boosting their risk for a variety of other health problems now and later in life.

One of these is atherosclerosis, a term that translates literally as hardening of the arteries. Atherosclerosis causes blood vessels that carry oxygen-rich blood throughout the body to become inflamed. White blood cells called macrophages settle in the vessel wall, which becomes overloaded with cholesterol. A plaque forms that restricts blood flow. But it remains a mystery how fat cells residing in one place in the body can trigger mayhem in cells and tissues located far away.

Small, lipid-lined sacs called extracellular vesicles (EVs), released by cells into the bloodstream, are likely troublemakers since they enable intercellular communication. Now, a multi-institutional team led by research faculty at Children’s National in Washington, D.C., finds that EVs derived from kids’ fat can play a pivotal role in ratcheting up risk for atherosclerotic cardiovascular disease well before any worrisome symptoms become visible. What’s more, the team showed that EVs found in the body’s fat stores can disrupt disposal of cholesterol in a variety of kids, from lean to obese, the team reports online July 22, 2019, in the Journal of Translational Medicine.

“We found that seven specific small sequences of RNA (microRNA) carried within the extracellular vesicles from human fat tissue impaired the ability of white blood cells called macrophages to eliminate cholesterol,” says Robert J. Freishtat, M.D., MPH, senior scientist at the Center for Genetic Medicine Research at Children’s National and the study’s senior author. “Fat isn’t just tissue. It can be thought of as a metabolic organ capable of communicating with types of cells that predispose someone to develop atherosclerotic cardiovascular disease, the leading cause of death around the world.”

Research scientists and clinicians from Children’s National, the George Washington University, NYU Winthrop Hospital and the National Heart, Lung and Blood Institute collaborated to examine the relationship between the content of EVs and their effect on macrophage behavior. Their collaborative effort builds on previous research that found microRNA derived from fat cells becomes pathologically altered by obesity, a phenomenon reversed by weight-loss surgery.

Because heart disease can have its roots in adolescence, they enrolled 93 kids aged 12 to 19 with a range of body mass indices (BMIs), including the “lean” group, 15 youth whose BMI was lower than 22 and the “obese” group, 78 youths whose BMI was in the 99th percentile for their age. Their median age was 17. Seventy-one were young women. They collected visceral adipose tissue during abdominal surgeries and visited each other’s respective labs to perform the experiments.

“We were surprised to find that EVs could hobble the macrophage cholesterol outflow system in adolescents of any weight,” says Matthew D. Barberio, Ph.D., the study’s lead author, a former Children’s National scientist who now is an assistant professor at the George Washington University’s Milken Institute School of Public Health. “It’s still an open question whether young people who are healthy can tolerate obesity—or whether there are specific differences in fat tissue composition that up kids’ risk for heart disease.”

The team plans to build on the current findings to safeguard kids and adults against future cardiovascular risk.

“This study was a huge multi-disciplinary undertaking,” adds Allison B. Reiss, M.D., of NYU Winthrop Hospital and the study’s corresponding author. “Ultimately, we hope to learn which properties belonging to adipose tissue EVs make them friendly or unfriendly to the heart, and we hope that gaining that knowledge will help us decrease morbidity and mortality from heart disease across the lifespan.”

In addition to Dr. Freishtat, additional study co-authors include Samuel B. Epstein, Madeleine Goldberg, Sarah C. Ferrante, and Evan P. Nadler, M.D., director of the Bariatric Surgery Program, all of Children’s National’s Center for Genetic Medicine Research; Lead Author, Matthew D. Barberio, of Millken Institute School of Public Health at the George Washington University; Lora J. Kasselman, Heather A. Renna, Joshua DeLeon, Iryna Voloshyna, Ashley Barlev, Michael Salama and Allison B. Reiss, all of NYU Winthrop Hospital; and Martin P. Playford and Nehal Mehta, of the National Heart, Lung and Blood Institute.

Financial support for research described in this post was provided by the National Institutes of Health National Center for Advancing Translational Sciences under award number UL1TR000075, the National Heart, Lung and Blood Institute under award number Z1AHL-06193-4, the American Heart Association under award number 17POST33670787, the Clark Charitable Foundation, the Elizabeth Daniel Research Fund, and Robert Buescher.

Dr. DeBiasi

Staying one step ahead of deadly Ebola

Dr. DeBiasi

An ongoing outbreak of Ebola virus since 2018 in the Democratic Republic of the Congo that has resulted in millions of travelers being screened at checkpoints, hundreds of thousands of vaccinations and thousands of deaths is a stark reminder of the need to remain one step ahead of the deadly disease.

To that end, one-half dozen personnel from Children’s National in Washington, D.C., including infectious diseases experts, critical care nurses and laboratory personnel traveled to New York in mid-August for an interactive workshop sponsored by the National Ebola Training and Education Center. They covered how to correctly don and doff protective gear, safely collect, handle and process specimens and discuss the special circumstances that arise when caring for pediatric patients, among other topics.

“Since 2014, Children’s National has evaluated 6 children with exposure as Persons Under Investigation of  Ebola virus disease, 4 of  whom required extended inpatient hospitalization under full isolation precautions,” says Roberta L. DeBiasi, M.D., MS, chief of the Division of Pediatric Infectious Diseases. “As a designated Ebola Treatment Center, we must continue our preparedness to care for additional patients with suspected and proven Ebola infection.

“Hands-on training and  drilling offer Children’s National personnel an opportunity to continue to test, evaluate and optimize our institutional Ebola response plan and procedures to maintain our preparedness for the needs of future patients,” adds Dr. DeBiasi.

In addition to Dr. DeBiasi, members of the Children’s National Special Pathogens Isolation Unit team who attended the Emerging Infectious Disease Workshop included:

  • Zohreh Hojjati, Laboratory Medicine.
  • Kristin Elizabeth Mullins, Clinical Lab Director, Laboratory Medicine.
  • Daniel Schroeder, Registered Nurse II, Pediatric Intensive Care Unit (PICU).
  • Melissa Taylor, Registered Nurse II, PICU.
  • Heather Wellman, Registered Nurse II, PICU.

“Among the keys to Children’s National serving as a national exemplar for pediatric Ebola care, is the stability of our multidisciplinary care team and our institutional commitment to ongoing training,” Dr. DeBiasi adds.

During a Grand Rounds presentation at Children’s National in mid-August, Dr. DeBiasi provided updates about recent global infectious disease outbreaks affecting pediatric patients including Ebola, measles, acute flaccid myelitis and Zika Virus. An interdisciplinary panel of Children’s National experts, including nurses, transport specialists, infectious disease and intensive care experts directly involved in caring for Ebola Persons Under Investigation, demonstrated personal protective equipment and fielded questions from staff. The overview also outlined Children’s National institutional expertise and response, including the Congenital Zika Virus Program, the Acute Flaccid Myelitis Task Force, the Special Isolation Unit for Ebola and other highly contagious infectious diseases.

Dr. Eurgenie Heitmiller

The origins of a go-to perioperative crisis app

Dr. Eurgenie Heitmiller

Children’s Chief of Anesthesiology and Pain Medicine, Dr. Heitmiller, was part of the team that originally launched the peer-reviewed perioperative crisis app, Pedi Crisis.

Around the same time that Atul Gawande and colleagues were developing adult operating room crisis checklists, a dedicated group of expert pediatric anesthesiologists were working on a set of checklists for pediatric specific, peer-reviewed algorithms to treat critical events in the perioperative setting.

Eugenie Heitmiller, M.D., chief of Anesthesiology, Pain and Perioperative Medicine at Children’s National Health System, was one of the initiators of what is known today as the Pedi Crisis App—a widely used reference tool designed to support clinician responses to life-threatening critical events.

Dr. Heitmiller and her colleagues on the Quality and Safety Committee of the Society for Pediatric Anesthesia (SPA) sought to create this series of standard algorithms that could be referenced both as teaching tools and as cognitive aids to be used in real time during rare critical occurrences in the perioperative setting.

“Most kids do well under anesthesia, but every once in a while, you have a child who has an event you don’t see that often, no matter how experienced you are,” she says. Having these checklists means we have a peer-reviewed, expert checklist at our fingertips.”

The original version of the checklists launched in 2010 as “Pediatric Critical Event Checklists”,  a Microsoft PowerPoint file that could be downloaded from the SPA website. Eventually, the checklists were adapted into an iPhone application as well as being translated into several languages.

Years after launch, these tools continue to be a mainstay for education, training, and critical event preparations for pediatric anesthesiologists and perioperative staff. A 2017 study found that in a three-month period of 2014, the app was accessed more than 4,000 times in 108 countries.

This year, the organizers of the joint SPA and American Academy of Pediatrics (AAP) meeting invited Dr. Heitmiller to moderate a panel that included talks on the launch of Pedi Crisis App 2.0 and its subsequent revisions. The newest edition of the Critical Events Checklists adds critical components including an updated smartphone app available for both the iPhone and Android, and the latest peer-reviewed content.

Pedi Crisis 2.0 also takes into account how people access and use the tool by incorporating elements that address human factors. The development team brought in  NASA senior research psychologist, Barbara Burian, Ph.D., to help make the content as intuitive as possible for quick access, accurate presentation, and recollection, even in a crisis. And, as Dr. Heitmiller points out, because pulling out a cell phone isn’t always the most realistic option in a sterile operating room environment, the content is always available for free outside of the mobile platform in a downloadable format on the SPA website so it can be accessed on any computer screen in any location.

Paradoxical outcomes for Zika-exposed tots

In the midst of an unprecedented Zika crisis in Brazil, there were a few flickers of hope: Some babies appeared to be normal at birth, free of devastating birth defects that affected other Brazilian children exposed to the virus in utero.

In the midst of an unprecedented Zika crisis in Brazil, there were a few flickers of hope: Some babies appeared to be normal at birth, free of devastating birth defects that affected other Brazilian children exposed to the virus in utero. But according to a study published online July 8, 2019, in Nature Medicine and an accompanying commentary co-written by a Children’s National clinician-researcher, the reality for Zika-exposed infants is much more complicated.

Study authors led by Karin Nielsen-Saines at David Geffen UCLA School of Medicine followed 216 infants in Rio de Janeiro who had been exposed to the Zika virus during pregnancy, performing neurodevelopmental testing when the babies ranged in age from 7 to 32 months. These infants’ mothers had had Zika-related symptoms themselves, including rash.

Although many children had normal assessments, 29% scored below average in at least one domain of neurological development, including cognitive performance, fine and gross motor skills and expressive language, Sarah B. Mulkey, M.D., Ph.D., and a colleague write in a companion commentary published online by Nature Medicine July 29, 2019.

The study authors found progressively higher risks for developmental, hearing and eye abnormality depending on how early the pregnancy was at the time the infants were exposed. Because Zika virus has an affinity for immature neurons, even babies who were not born with microcephaly remained at continued risk for suffering abnormalities.

Of note, 24 of 49 (49%) infants who had abnormalities at birth went on to have normal test results in the second or third year of life. By contrast, 17 of 68 infants (25%) who had normal assessments at birth had below-average developmental testing or had abnormalities in hearing or vision by age 32 months.

“This work follows babies who were born in 2015 and 2016. It’s heartening that some babies born with abnormalities tested in the normal range later in life, though it’s unclear whether any specific interventions help to deliver these positive findings,” says Dr. Mulkey, a fetal–neonatal neurologist in the Division of Fetal and Transitional Medicine at Children’s National in Washington, D.C. “And it’s quite sobering that babies who appeared normal at birth went on to develop abnormalities due to that early Zika exposure.”

It’s unclear how closely the findings apply to the vast majority of U.S. women whose Zika infections were asymptomatic.

“This study adds to the growing body of research that argues in favor of ongoing follow-up for Zika-exposed children, even if their neurologic exams were reassuring at birth,” Dr. Mulkey adds. “As Zika-exposed children approach school age, it’s critical to better characterize the potential implications for the education system and public health.”

In addition to Dr. Mulkey, the perspective’s senior author, William J. Muller, Northwestern University, was the commentary’s lead author.

ID-KD vaccine induced T-cell cytotoxicity

Fighting lethal cancer with a one-two punch

The immune system is the ultimate yin and yang, explains Anthony D. Sandler, M.D., senior vice president and surgeon-in-chief of the Joseph E. Robert Jr. Center for Surgical Care at Children’s National in Washington, D.C. With an ineffective immune system, infections such as the flu or diarrheal illness can run unchecked, causing devastating destruction. But on the other hand, excess immune activity leads to autoimmune diseases, such as lupus or multiple sclerosis. Thus, the immune system has “checks and balances” to stay controlled.

Cancer takes advantage of “the checks and balances,” harnessing the natural brakes that the immune system puts in place to avoid overactivity. As the cancer advances, molecular signals from tumor cells themselves turn on these natural checkpoints, allowing cancers to evade immune attack.

Several years ago, a breakthrough in pharmaceutical science led to a new class of drugs called checkpoint inhibitors. These medicines take those proverbial brakes off the immune system, allowing it to vigorously attack malignancies. However, Dr. Sandler says, these drugs have not worked uniformly and in some cancers, they barely work at all against the cancer.

One of these non-responders is high risk neuroblastoma, a common solid tumor found outside the skull in children. About 800 U.S. children are diagnosed with this cancer every year. And kids who have the high-risk form of neuroblastoma have poor prognoses, regardless of which treatments doctors use.

However, new research could lead to promising ways to fight high-risk neuroblastoma by enabling the immune system to recognize these tumors and spark an immune response. Dr. Sandler and colleagues recently reported on these results in the Jan. 29, 2018, PLOS Medicine using an experimental model of the disease.

The researchers created this model by injecting the preclinical models with cancer cells from an experimental version of neuroblastoma. The researchers then waited several days for the tumors to grow. Samples of these tumors showed that they expressed a protein on their cell surfaces known as PD-L1, a protein that is also expressed in many other types of human cancers to evade immune system detection.

To thwart this protective feature, the researchers made a cancer vaccine by removing cells from the experimental model’s tumors and selectively turning off a gene known as Id2. Then, they irradiated them, a treatment that made these cells visible to the immune system but blocked the cells from dividing to avoid new tumors from developing.

They delivered these cells back to the experimental models, along with two different checkpoint inhibitor drugs – antibodies for proteins known as CLTA-4 and PD-L1 – over the course of three treatments, delivered every three days. Although most checkpoint inhibitors are administered over months to years, this treatment was short-term for the experimental models, Dr. Sandler explains. The preclinical models were completely finished with cancer treatment after just three doses.

Over the next few weeks, the researchers witnessed an astounding turnaround: While experimental models that hadn’t received any treatment uniformly died within 20 days, those that received the combined vaccine and checkpoint inhibitors were all cured of their disease. Furthermore, when the researchers challenged these preclinical models with new cancer cells six months later, no new tumors developed. In essence, Dr. Sandler says, the preclinical models had become immune to neuroblastoma.

Further studies on human patient tumors suggest that this could prove to be a promising treatment for children with high-risk neuroblastoma. The patient samples examined show that while tumors with a low risk profile are typically infiltrated with numerous immune cells, tumors that are high-risk are generally barren of immune cells. That means they’re unlikely to respond to checkpoint inhibiting drugs alone, which require a significant immune presence in the tumor microenvironment. However, Dr. Sandler says, activating an immune response with a custom-made vaccine from tumor cells could spur the immune response necessary to make these stubborn cancers respond to checkpoint inhibitors.

Dr. Sandler cautions that the exact vaccine treatment used in the study won’t be feasible for people. The protocol to make the tumor cells immunogenic is cumbersome and may not be applicable to gene targeting in human patients. However, he and his team are currently working on developing more feasible methods for crafting cancer vaccines for kids. They also have discovered a new immune checkpoint molecule that could make this approach even more effective.

“By letting immune cells do all the work we may eventually be able to provide hope for patients where there was little before,” Dr. Sandler says.

In addition to Dr. Sandler, study co-authors include Priya Srinivasan, Xiaofang Wu, Mousumi Basu and Christopher Rossi, all of the Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation (SZI), at Children’s National in Washington, D.C.

Financial support for research described in this post was provided by the EVAN Foundation, the Catherine Blair foundation, the Michael Sandler Research Fund and SZI.

ID-KD vaccine induced T-cell cytotoxicity

Mechanism of Id2kd Neuro2a vaccination combined with α-CTLA-4 and α-PD-L1 immunotherapy in a neuroblastoma model. During a vaccine priming phase, CTLA-4 blockade enhances activation and proliferation of T-cells that express programmed cell death 1 (PD1) and migrate to the tumor. Programmed cell death-ligand 1 (PD-L1) is up-regulated on the tumor cells, inducing adaptive resistance. Blocking PD-L1 allows for enhanced cytotoxic effector function of the CD8+ tumor-infiltrating lymphocytes. Artist: Olivia Abbate

zika virus

Neuroimaging essential for Zika cases

zika virus

About three years ago, Zika virus emerged as a newly recognized congenital infection, and a growing body of research indicates the damage it causes differs from other infections that occur in utero.

Seventy-one of 110 Brazilian infants at the highest risk for experiencing problems due to exposure to the Zika virus in the womb experienced a wide spectrum of brain abnormalities, including calcifications and malformations in cortical development, according to a study published July 31, 2019 in JAMA Network Open.

The infants were born at the height of Brazil’s Zika epidemic, a few months after the nation declared a national public health emergency. Already, many of the infants had been classified as having the severe form of congenital Zika syndrome, and many had microcephaly, fetal brain disruption sequence, arthrogryposis and abnormal neurologic exams at birth.

These 110 infants “represented a group of ZIKV-exposed infants who would be expected to have a high burden of neuroimaging abnormalities, which is a difference from other reported cohorts,” Sarah B. Mulkey, M.D., Ph.D., writes in an invited commentary published in JAMA Network Open that accompanies the Rio de Janeiro study. “Fortunately, many ZIKV-exposed infants do not have abnormal brain findings or a clinical phenotype associated with congenital Zika syndrome,” adds Dr. Mulkey, a fetal–neonatal neurologist in the Division of Fetal and Transitional Medicine at Children’s National in Washington, D.C.

Indeed, a retrospective cohort of 82 women exposed to Zika during their pregnancies led by a research team at Children’s National found only three pregnancies were complicated by severe fetal brain abnormalities. Compared with the 65% abnormal computed tomography (CT) or magnetic resonance imaging (MRI) findings in the new Brazilian study, about 1 in 10 (10%) of babies born to women living in the continental U.S. with confirmed Zika infections during pregnancy had Zika-associated birth defects, according to the Centers for Disease Control and Prevention.

“There appears to be a spectrum of brain imaging abnormalities in ZIKV-exposed infants, including mild, nonspecific changes seen at cranial US [ultrasound], such as lenticulostriate vasculopathy and germinolytic cysts, to more significant brain abnormalities, such as subcortical calcifications, ventriculomegaly and, in its most severe form, thin cortical mantle and fetal brain disruption sequence,” Dr. Mulkey writes.

About three years ago, Zika virus emerged as a newly recognized congenital infection, and a growing body of research indicates the damage it causes differs from other infections that occur in utero. Unlike congenital cytomegalovirus infection, cerebral calcifications associated with Zika are typically subcortical, Dr. Mulkey indicates. What’s more, fetal brain disruption sequence seen in Zika-exposed infants is unusual for other infections that can cause microcephaly.

“Centered on the findings of Pool, et al, and others, early neuroimaging remains one of the most valuable investigations of the Zika-exposed infant,” Dr. Mulkey writes, including infants who are not diagnosed with congenital Zika syndrome.  She recommends:

  • Cranial ultrasound as the first-line imaging option for infants, if available, combined with neurologic and ophthalmologic exams, and brainstem auditory evoked potentials
  • Zika-exposed infants with normal cranial ultrasounds do not need additional imaging unless they experience a developmental disturbance
  • Zika-exposed infants with abnormal cranial ultrasounds should undergo further neuroimaging with low-dose cranial CT or brain MRI.

Autonomic nervous system appears to function well regardless of mode of childbirth

Late in pregnancy, the human body carefully prepares fetuses for the rigors of life outside the protection of the womb. Levels of cortisol, a stress hormone, ramp up and spike during labor. Catecholamines, another stress hormone, also rise at birth, helping to kick start the necessary functions that the baby will need to regulate breathing, heartbeat, blood pressure and energy metabolism levels at delivery. Oxytocin surges, promoting contractions for the mother during labor and stimulating milk production after the infant is born.

These processes also can play a role in preparing the fetal brain during the transition to life outside the womb by readying the autonomic nervous system and adapting its cerebral connections. The autonomic nervous system acts like the body’s autopilot, taking in information it needs to ensure that internal organs run steadily without willful action, such as ensuring the heart beats and eyelids blink at steady intervals. Its yin, the sympathetic division, stimulates body processes while its yang, the parasympathetic division, inhibits them.

Infants born preterm have reduced autonomic function compared with their full-term peers and also face possible serious neurodevelopmental impairment later in life. But is there a difference in autonomic nervous system function for full-term babies after undergoing labor compared with infants delivered via cesarean section (C-section)?

A team from the Children’s National Inova Collaborative Research Program (CNICA) – a research collaboration between Children’s National in Washington, D.C., and Inova Women’s and Children’s Hospital in Virginia – set out to answer that question in a paper published online July 30, 2019, in Scientific Reports.

They enrolled newborns who had experienced normal, full-term pregnancies and recorded their brain function and heart performance when they were about 2 days old. Infants whose conditions were fragile enough to require observation in the neonatal intensive care unit were excluded from the study. Of 167 infants recruited for the prospective cohort study, 118 newborns had sufficiently robust data to include them in the research.  Of these newborns:

  • 62 (52.5%) were born by vaginal delivery
  • 22 (18.6%) started out with vaginal delivery but ultimately switched to C-section based on failure to progress, failed labor induction or fetal intolerance to labor
  • And 34 (28.8%) were born by elective C-section.

The CNICA research team swaddled infants for comfort and slipped electrode nets over their tiny heads to simultaneously measure heart rate variability and electrocortical function through non-invasive techniques. The team hypothesized that infants who had been exposed to labor would have enhanced autonomic tone and higher cortical electroencephalogram (EEG) power than babies born via C-section.

“In a low-risk group of babies born full-term, the autonomic nervous system and cortical systems appear to function well regardless of whether infants were exposed to labor prior to birth,” says Sarah B. Mulkey, M.D., Ph.D., a fetal–neonatal neurologist in the Division of Fetal and Transitional Medicine at Children’s National and the study’s lead author.

However, infants born by C-section following a period of labor had significantly increased accelerations in their heart rates. And the infants born by C-section during labor had significantly lower relative gamma frequency EEG at 25.2 hours old compared with the other two groups studied.

“Together these findings point to a possible increased stress response and arousal difference in infants who started with vaginal delivery and finished delivery with C-section,” Dr. Mulkey says. “There is so little published research about the neurologic impacts of the mode of delivery, so our work helps to provide a normal reference point for future studies looking at high-risk infants, including babies born preterm.”

Because the research team saw little differences in autonomic tone or other EEG frequencies when the infants were 1 day old, future research will explore these measures at different points in the newborns’ early life as well as the role of the sleep-wake cycle on heart rate variability.

In addition to Dr. Mulkey, study co-authors include Srinivas Kota, Ph.D., Rathinaswamy B. Govindan, Ph.D., Tareq Al-Shargabi, MSc, Christopher B. Swisher, BS, Laura Hitchings, BScM, Stephanie Russo, BS, Nicole Herrera, MPH, Robert McCarter, ScD, and Senior Author Adré  J. du Plessis, M.B.Ch.B., MPH, all of Children’s National; and Augustine Eze Jr., MS, G. Larry Maxwell, M.D., and Robin Baker, M.D., all of Inova Women’s and Children’s Hospital.

Financial support for research described in this post was provided by the National Institutes of Health National Center for Advancing Translational Sciences under award numbers UL1TR001876 and KL2TR001877.