Allergy & Immunology

chromosome

X-linked genes help explain why boys of all ages face higher respiratory risk

chromosome

A multi-institution research team that includes Children’s National Health System attempted to characterize gender-based epigenomic signatures in the human airway early in children’s lives with a special attention to defining DNA methylation patterns of the X chromosome.

Human airways already demonstrate gender-based differences in DNA methylation signatures at birth, providing an early hint of which infants may be predisposed to develop respiratory disorders like asthma later in life, a research team reports in a paper published online April 3, 2018, in Scientific Reports.

It’s clear that boys and young men are more likely to develop neonatal respiratory distress syndrome, bronchopulmonary dysplasia, viral bronchiolitis, pneumonia, croup and childhood asthma. Unlike boys, girls have an additional copy of the X chromosome, which is enriched with immune-related genes, some of which play key roles in the development of respiratory conditions. Methylation prevents excessive gene activity in X-linked genes, however much remains unknown about how this process influences infants’ risk of developing airway diseases.

A multi-institution research team that includes Children’s National Health System attempted to characterize gender-based epigenomic signatures in the human airway early in children’s lives with a special attention to defining DNA methylation patterns of the X chromosome.

“It’s clear as we round in the neonatal intensive care unit that baby boys remain hospitalized longer than girls and that respiratory ailments are quite common. Our work provides new insights about gender differences in airway disease risk that are pre-determined by genetics,” says Gustavo Nino, M.D., a Children’s pulmonologist and the study’s senior author.

“Characterizing early airway methylation signatures holds the promise of clarifying the nature of gender-based disparities in respiratory disorders and could usher in more personalized diagnostic and therapeutic approaches.”

The research team enrolled 12 newborns and infants in the study and obtained their nasal wash samples. Six of the infants were born preterm, and six were born full term. The researchers developed a robust gender classification algorithm to generate DNA methylation signals. The machine learning algorithm identified X-linked genes with significant differences in methylation patterns in boys, compared with girls.

As a comparison group, they retrieved pediatric nasal airway epithelial cultures from a study that looked at genomic DNA methylation patterns and gene expression in 36 children with persistent atopic asthma compared with 36 heathy children.

The team went on to classify X-linked genes that had significant gender-based X methylation and those genes whose X methylation was variable.

“These results confirm that the X chromosome contains crucial information about gender-related genetic differences in different airway tissues,” Dr. Nino says. “More detailed knowledge of the genetic basis for gender differences in the respiratory system may help to predict, prevent and treat respiratory disorders that can affect patients over their entire lifetimes.”

In addition to Dr. Nino, study co-authors include Lead Author Cesar L. Nino, bioinformatics scientist, Pontificia Universidad Javeriana; Geovanny F. Perez, M.D., co-director of Children’s Severe Bronchopulmonary Dysplasia Program; Natalia Isaza Brando, M.D., Children’s neonatology attending; Maria J. Gutierrez, Johns Hopkins University School of Medicine; and Jose L. Gomez, Yale University School of Medicine.

Financial support for this research was provided by the National Institutes of Health under award numbers AI130502-01A1, HL090020, HL125474-03, HD001399, UL1TR000075 and KL2TR000076.

Anthony Sandler

Anthony Sandler, M.D., Named Director of Sheikh Zayed Institute

Anthony Sandler

Children’s National Health System is pleased to announce that Anthony Sandler, M.D., current senior vice president and surgeon-in-chief of the Joseph E. Robert Jr. Center for Surgical Care at Children’s National, will now additionally assume the title of director, Sheikh Zayed Institute for Pediatric Surgical Innovation. He will succeed Peter Kim, M.D., the founding vice president of the Sheikh Zayed Institute, who is leaving to pursue other career opportunities after seven years at the helm of our surgical innovation center.

Dr. Sandler will be in a unique position, leading both in the research and clinical enterprises of Children’s National and will help to forge a stronger link between them, especially in the surgical subspecialties.

Internationally known for his work on childhood solid tumors and operative repair of congenital anomalies, Dr. Sandler is the Diane and Norman Bernstein Chair in Pediatric Surgery and is a professor of surgery and pediatrics at the George Washington University School of Medicine & Health Sciences. He is currently on the Board of Examiners for the Pediatric Surgery Qualifying Examination and has served on multiple committees for the American Pediatric Surgical Association and for the Children’s Oncology Group.

Dr. Sandler’s research interests focus on solid tumors of childhood and he’s presently studying tumor immunology and investigating immunotherapeutic vaccine strategies. He has co-developed a surgical polymer sealant that is R01 funded by the National Institutes of Health and is currently in pre-clinical trials. Dr. Sandler has over 120 peer-reviewed publications in clinical and scientific medical journals.

Kavita Parikh

Discharge strategies to prevent asthma readmissions

“Improving how we care for children who are hospitalized with asthma includes preparing them for a successful return home with the best tools to manage their illness and prevent a future hospital visit,” says Kavita Parikh, M.D., M.S.H.S.

Readmission rates at three months for kids hospitalized for acute asthma dropped when families received comprehensive education prior to discharge, the only single component of discharge bundles that was strongly associated with lowered readmissions, finds a multicenter retrospective cohort study published online Feb. 1, 2018, in The Journal of Pediatrics.

According to the Centers for Disease Control and Prevention, asthma is the most common chronic lung disease of childhood, affecting roughly 6 million U.S. children. Hospitalization for asthma accounts for $1.5 billion in annual hospital charges and represents almost one-third of childhood asthma costs.

Children who are hospitalized for asthma have a roughly 20 percent chance of returning to the hospital in the next year, and individual hospital readmission rates can range from 5.7 percent to 9.1 percent at three months, writes the study team. While the National Institutes of Health (NIH) has published evidence-based guidelines for discharge planning, there is no single, standardized asthma discharge process used across all pediatric hospitals in the U.S. that impacts 30-day readmission rates.

“Improving how we care for children who are hospitalized with asthma includes preparing them for a successful return home with the best tools to manage their illness and prevent a future hospital visit,” says Kavita Parikh, M.D., M.S.H.S., an associate professor of pediatrics at Children’s National Health System and lead study author. “Our study underscores the importance of increasing the intensity of select discharge components. For example, ensuring that children hospitalized for asthma receive asthma medication at discharge along with comprehensive education and environmental mitigation may reduce asthma readmissions.”

The study team analyzed records from a national sample of tertiary care children’s hospitals, looking at hospitalizations of 5- to 17-year-olds for acute asthma exacerbation during the 2015 calendar year. They characterized how frequently hospitals used 13 separate asthma discharge components by distributing an electronic survey to quality leaders. Forty-five of 49 hospitals (92 percent) completed the survey.

The 45 hospitals recorded a median of 349 asthma discharges per year and had a median adjusted readmission rate of 2.6 percent at 30 days and a 6.6 percent median adjusted readmission rate at three months. The most commonly used discharge components employed for children with asthma were having a dedicated person providing education (76 percent), providing a spacer at discharge (67 percent) and communicating with a primary medical doctor (58 percent).

Discharge components that were trending toward reduced readmission rates at three months include:

  • Comprehensive asthma education, including having dedicated asthma educators
  • Medications and devices provided to patients at discharge, such as spacers, beta-agonists, controller medication and oral steroids
  • Communication and scheduled appointments with a primary medical doctor
  • Post-discharge activities, including home visits and referrals for environmental mitigation programs.

“In addition to being aligned with NIH asthma recommendations, connecting the family with a primary care provider after discharge helps to improve patients’ timely access to care if symptoms recur when they return home,” Dr. Parikh adds. “Bundling these discharge components may offer multiple opportunities to educate patients and families and to employ a range of communication styles such as didactic, visual and interactive.”

Study co-authors include Matt Hall, Ph.D., Children’s Hospital Association; Chén C. Kenyon, M.D., M.S.H.P., The Children’s Hospital of Philadelphia; Ronald J. Teufel II, M.D., M.S.C.R., Medical University of South Carolina; Grant M. Mussman, M.D., M.H.S.A. and Samir S. Shah, M.D., M.S.C.E., Cincinnati Children’s Hospital Medical Center; Amanda Montalbano, M.D., M.P.H., Children’s Mercy; Jessica Gold, M.D., M.S., Lucile Packard Children’s Hospital Stanford; James W. Antoon, M.D., Children’s Hospital; Anupama Subramony, M.D., Cohen Children’s Medical Center; Vineeta Mittal, M.D., M.B.A. and Rustin B. Morse, M.D., Children’s Health; and Karen M. Wilson, M.D., M.P.H., Icahn School of Medicine at Mount Sinai.

Research reported in this post was supported by the Agency for Healthcare Research and Quality, K08HS024554.

Stephen Teach

Stephen Teach, M.D., M.P.H., named associate dean at GW School of Medicine and Health Sciences

Stephen Teach

Stephen J. Teach, M.D., M.P.H., chair of the Department of Pediatrics at Children’s National Health System, was named associate dean for Pediatric Academic Affairs at The George Washington University (GW) School of Medicine and Health Sciences.

Dr. Teach is director and principal investigator of Improving Pediatric Asthma Care in the District of Columbia (IMPACT DC), a care, research and advocacy program focused on helping under-resourced and largely minority children who suffer from asthma. He also serves as principal investigator for the Washington site for the Inner City Asthma Consortium, funded by the National Institutes of Health.

At GW, Dr. Teach will play a critical role in supporting and enhancing education and training relationships between the university and Children’s National and will support the academic advancement of Children’s National faculty. Read more.

Human Rhinovirus

When a common cold may trigger early supportive care

Human Rhinovirus

A new study led by Children’s National Health System shows that in infants who were born severely premature, human rhinovirus infections appear to trigger airway hyper-reactivity, which leads to wheezing, hyperinflation and more severe respiratory disease.

Human rhinovirus (HRV), the culprit behind most colds, is the leading cause of hospitalization for premature babies. However, in very preterm children, exactly how HRV causes severe respiratory disease – and which patients may need more intensive observation and treatment – is less well understood.

A new study led by Children’s National Health System research-clinicians showed in children who were born severely premature, HRV infections seem to trigger an airway hyper-reactivity (AHR) type of disease, which leads to wheezing and air-trapping (hyperinflation) and more severe respiratory disease. This, in turn, increases the risk for hospitalization.

The study, published online Oct. 21, 2017 in Pediatrics and Neonatology, found that other signs of respiratory distress, such as low arterial blood oxygen or rapid shallow breathing, were no more common in severely premature children (less than 32 weeks of gestational age) than in kids born preterm or full-term. The findings have implications for administering supportive care sooner or more intensively for severely premature children than for other infants.

“When it comes to how they respond to such infections, severely premature children are quite different,” says Geovanny Perez, M.D., a specialist in pulmonary medicine at Children’s National and lead study author. “We’ve known they are more susceptible to human rhinovirus infection and have more severe disease. However, our study findings suggest that severely premature kids have an ‘asthma’ type of clinical picture and perhaps should be treated differently.”

The study team sought to identify clinical phenotypes of HRV infections in young children hospitalized for such infections. The team theorized that severely premature babies would respond differently to these infections and that their response might resemble symptoms experienced by patients with asthma.

“For a number of years, our team has studied responses to viruses and prematurity, especially HRV and asthma,” Dr. Perez says. “We know that premature babies have an immune response to HRV from the epithelial cells, similar to that seen in older patients with asthma. But we wanted to address a gap in the research to better understand which children may need closer monitoring and more supportive care during their first HRV infection.”

Geovanny Perez

“When it comes to how they respond to such infections, severely premature children are quite different,” says Geovanny Perez, M.D. “We’ve known they are more susceptible to human rhinovirus infection and have more severe disease. However, our study findings suggest that severely premature kids have an ‘asthma’ type of clinical picture and perhaps should be treated differently.”

In a retrospective cross-sectional analysis, the study looked at 205 children aged 3 years or younger who were hospitalized at Children’s National in 2014 with confirmed HRV infections. Of these, 71 percent were born full-term (more than 37 gestational weeks), 10 percent were preterm (32 to 37 gestational weeks) and 19 percent were severely premature (less than 32 gestational weeks).

Dr. Perez and his team developed a special respiratory distress scoring system based on physical findings in the children’s electronic medical records to assess the degree of lower-airway obstruction or AHR (as occurs in asthma) and of parenchymal lung disease. The physical findings included:

  • Wheezing;
  • Subcostal retraction (a sign of air-trapping/hyperinflation of the lungs), as can occur in pneumonia;
  • Reduced oxygen levels (hypoxemia); and
  • Increased respiratory rate (tachypnea).

The research team assigned each case an overall score. The severely premature children had worse overall scores – and significantly worse scores for AHR and hyperinflated lungs relative to children born late preterm or full-term.

“What surprised us, though, in this study was that the phenotypical characterization using individual parameters for parenchymal lung disease, such as hypoxemia or tachypnea, were not different in severe preterm children and preterm or full term,” says Dr. Perez. “On the other hand, our study found that severely preterm children had a lower airway obstruction phenotype associated with retractions and wheezing. Moreover there was a ‘dose effect’ of prematurity: Children who were born more premature had a higher risk of wheezing and retractions.”

Among the implications of this study, Dr. Perez sees the potential to use phenotypical (clinical markers, such as retractions and wheezing) and biological biomarkers to better personalize patients’ treatments. Dr. Perez and his team have identified biological biomarkers in nasal secretions of children with rhinovirus infection that they plan to combine with clinical biomarkers to identify which patients with viral infections will benefit from early supportive care, chronic treatments or long-term monitoring.

Dr. Perez says further research in this area should pursue a number of paths, including:

  • A longitudinal study to elucidate which children will benefit from asthma-like treatment, such as bronchodilators or corticosteroids;
  • A study of biomarkers, including microRNAs and other inflammatory molecules; or
  • Alternatively, a longitudinal study exploring the mechanism by which wheezing develops, perhaps looking at first and subsequent rhinovirus infections in babies born at different gestational ages.

Children’s National Chief of Allergy and Immunology helps move gene therapy forward

Catherine Bollard

Catherine Bollard, M.D., MBChB, Chief of the Division of Allergy and Immunology, recently shared her expertise on an FDA panel that unanimously expressed its support for a pediatric cancer T-cell therapy called CTL019.

On July 12, 2017, a U.S. Food and Drug Administration advisory committee unanimously expressed its support for CTL019 – a pediatric cancer T-cell therapy. If the FDA follows the advice from the 10-member Oncologic Drug Advisory Committee (ODAC) – which included Children’s National Health System’s Catherine Bollard, M.D., MBChB, Chief of the Division of Allergy and Immunology and Director of the Program for Cell Enhancement and Technologies for Immunotherapy – CTL019 will become the first gene therapy to hit the market.

“Many of these children with recurrent cancer are out of other options to treat their illness,” said Dr. Bollard. “We are encouraged by these findings and the potential for this therapy to improve outcomes and quality of life.”

CTL019 is a chimeric antigen receptor (CAR) T-cell therapy, comprised of genetically modified T cells that target CD19, an antigen expressed on the surface of B cells. Also known as tisagenlecleucel, the therapy targets a single type of cancer called acute lymphoblastic leukemia and was created by Novartis.

In clinical trials, CTL019 showed unparalleled effectiveness. Of the 68 patients who received the drug, 52 responded almost immediately, and their cancer disappeared within the first three months. Seventy-five percent of those patients remained cancer-free six months after treatment. The therapy has one main side effect: an immune reaction called cytokine release syndrome, which can be deadly, with extended spiking fevers and other symptoms.

However, because of CTL019’s high efficacy, FDA scientists asked the ODAC panel to focus on the therapy’s safety and manufacturing challenges rather than whether or not it works.

Several committee members, including Dr. Bollard, expressed apprehension about the T-cell subpopulations’ heterogeneity, which could affect safety and efficacy. Another issue for consideration by the ODAC panel was the long-term side effects of CTL019 and the possibility that the T-cell modification could go awry, causing secondary cancers in the future.

Despite these concerns, the committee concluded that the strong efficacy data and the near-term benefits of CAR-T therapy more than tipped the scales in favor of the therapy. ODAC members were also pleased with Novartis’ plan to minimize risk, which includes limiting CTL019 distribution to selected centers with CAR T-cell therapy experience, and extensive, long-term post-marketing surveillance plans.

The FDA is not required to follow the ODAC panel’s advice when making its final decision, but it often does so. A final decision by the FDA is anticipated by late September.

Read more about the story in the Philadelphia Inquirer, Medpage Today and Healio.com.

asthma medication delivery

School’s in for asthma medication adherence

asthma medication delivery

A research team from Children’s National tried to reduce missed doses of daily medications, improve asthma control and tamp down on schoolchildren’s asthma attacks by outsourcing morning delivery of inhaled corticosteroids to the school nurse.

Doctors and researchers have long known that the level of stress patients experience is inversely linked to how adherent they are with taking medications: The higher the stress, the less likely patients are to take doses of their medication correctly, on time or at all. For families of school-aged children, there are few times more stressful than mornings, when parents or caregivers need to get kids ready for their school day, pack everything they need and get them out the door on time.

These stressful mornings, says Stephen J. Teach, M.D., M.P.H., chair of the Department of Pediatrics at Children’s National Health System, can spell danger for children with persistent asthma. This chronic condition is typically treated with nightly and morning doses of inhaled corticosteroids (ICS), medications that decrease lung inflammation to prevent asthma attacks. When children miss a morning dose because their families are too busy, their asthma symptoms can exacerbate, causing them to miss school, be unable to participate in activities like sports or lose sleep at night.

But Dr. Teach and colleagues had a simple idea to bypass the morning struggle for many families: Instead of trying to fit delivery of ICS into an already packed schedule, why not outsource it to the school nurse?

“We thought that if we could have those morning doses administered by these medically trained individuals with great technique and regularity, then maybe we would see some improved outcomes in kids,” Dr. Teach says. “And we did, in a striking way.”

Dr. Teach and colleagues recruited 46 children to participate in a pilot study, published online June 8, 2017 in the Journal of Asthma. To be eligible, these participants had to be in grades kindergarten through eighth in the Washington, D.C. public school system and on Medicaid, demonstrating the type of financial need that can add to the cumulative stress a family already faces. The children were scattered across 18 schools.

“We thought that if we could have those morning doses administered by these medically trained individuals with great technique and regularity, then maybe we would see some improved outcomes in kids,” Dr. Teach says. “And we did, in a striking way.”

Twenty-one of these participants received morning doses of ICS (the intervention group), which the researchers provided to school nurses along with an asthma action plan. The rest (the control group) remained on their prescribed morning and evening doses at home.

After 60 days, the researchers followed up with schools and families. Through electronic records kept by each school, the researchers found that the intervention group received more than 90 percent of their prescribed morning doses—about the same number reported by parents of the control group. However, the two groups demonstrated impressive differences in quality-of-life measures:

  • While about 24 percent of the intervention group missed one or fewer days of school due to asthma during the 60-day trial, about 44 percent of the control group did.
  • About 43 percent of the intervention group reported functional limitations due to their asthma, compared with 74 percent of the control group.
  • The intervention group reported only 1.7 nights with asthma-related sleep loss in the previous two weeks, compared with 4.1 nights in the control group.
  • Additionally, only about one-quarter of the intervention group required adjustments in family life to accommodate their asthma, compared with more than one-half of the control group.

The reasons for these differences aren’t clear, says Dr. Teach. But he and colleagues suggest that they might be due to over-reporting of how many doses were delivered at home in the control group or improper administration of these drugs at home.

Regardless, he says, the results show that this type of school-based intervention was not only feasible for children, school nurses and families, but also led to numerous positive health outcomes for the participants who received it. Based on the results of this study, Dr. Teach and colleagues have started to prescribe school-based administration of morning ICS doses to families interested in receiving them as a new standard of care.

“These data, combined with data from similar studies at other institutions, suggest that school-based therapy is increasingly becoming a very real and proven option for clinicians and families when adherence is a struggle,” he says.

Catherine Bollard named to Medicine Maker’s Annual Power List

Catherine Bollard

Children’s National Health System’s Chief of Allergy and Immunology, Catherine Bollard M.D., has been named to The Medicine Maker’s 2017 Power List, which honors the top 100 most influential people in the world of drug development. Dr. Bollard is featured as a ”Champion of Change,” a category that highlights experts striving to make the world a better place by getting medicines to those who need them the most. She joins notable scientists Frances Collins, director of the U.S. National Institutes of Health, and Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases.

In the Medicine Maker feature, Dr. Bollard describes the inspiration behind her dedication to cellular immunotherapy and how that led to her team’s breakthrough T-cell therapy that gives complete remissions in over 50 percent of some patient groups. Read the full piece here.

Cell therapy virtuoso: Catherine Bollard

Catherine Bollard

In the Medicine Maker piece, Cell Therapy Virtuoso, Children’s National Medical System’s Chief of Allergy and Immunology, Catherine Bollard M.D., discusses why she chose a career in medicine, the personal experience that ignited her interest in cell therapies, and her insights on the current state and future of the immunotherapy field. Highlights from the interview include:

  • On the promise of T-cell therapy: “We’ve now developed several T-cell therapies that give complete remission rates of approximately 75% and two-year progression-free survival rates ranging from 50 percent to over 90 percent depending on the patient population.”
  • Regarding the future of immunotherapy: “The field has expanded dramatically over the last 25 years. In particular, T-cell therapies for cancer have grown rapidly and now the field is expanding into other areas, such as regulatory T-cells for autoimmune disease and virus T-cells for HIV. Given what the immune system can do, the applications are almost limitless.”

Dr. Bollard was featured for her role as president of the International Society for Cellular Therapy.

Patrick Hanley receives prestigious Manasevit Research Scholar Grant

Patrick Hanley, Ph.D

Patrick Hanley, Ph.D., will receive the award at the ASBMT national meeting in late February 2017.

The American Society of Blood and Marrow Transplantation and the National Marrow Donor Program have awarded the Amy Strelzer Manasevit Research Scholar grant award to Children’s National researcher Patrick J. Hanley.

Hanley, Ph.D., Laboratory Facility Director, Cellular Therapy and Stem Cell Processing and Assistant Professor of Pediatrics at The George Washington University, will receive the award at ASBMT national meeting in late February 2017. It is the first time a Children’s National staff member has been awarded this grant, which is for $240,000 over three years.

The Amy research program is one of the largest and most coveted research grants in the field of marrow and cord blood transplantation, according to the program’s website.

“The program develops the next generation of physician-scientists by supporting and encouraging the discovery of new ways to treat and prevent post-transplant complications,” the program reports.

Hanley plans to use the grant to treat patients on their upcoming clinical trial, “CHEERS”, which is for patients receiving a cord blood transplant. These patients will receive immune cells that were expanded from cord blood, called T cells, that have been trained in the lab to target viruses – a major complication after transplant.

“This grant enables us to evaluate whether cord blood T cells that recognize viruses like CMV and now BK virus can offer protection to patients who need it most,” Hanley says.

Learn more about the grant program.

asthma inhailer

A successful patient-centered asthma study

A study by Stephen Teach, M.D., M.P.H., shows that extensively engaging stakeholders such as parents, families and local service providers in study design can transform a planned research project into a more patient-centered study.

For hundreds of years, scientific and medical research has followed a process that practically all grade-school children learn as the scientific method: Scientists make observations that lead to a question. After developing a hypothesis, the researchers and colleagues — usually other scientists in the same field — test it by gathering data from experiments, making more observations or searching through the existing literature. Once they have an answer, the researchers often publish it in a scientific journal, which can generate new questions among peer scientists and starts the cycle all over again.

While most research is meant to benefit humankind as a whole, non-scientists and people who aren’t research subjects usually aren’t involved much in the process itself. That can be a serious omission, particularly for medical research, says Stephen J. Teach, M.D., M.P.H., chair of the Department of Pediatrics at Children’s National Health System, and Deborah Quint Shelef, M.P.H., C.C.R.P., AE-C., program director at IMPACT DC, a program at Children’s National Health System that helps patients effectively manage asthma.

“Our patients might view research a little differently than we do. They don’t just want general contributions to knowledge, but specific contributions that people can actually use,” Shelef says. “One of our main goals is to have useful research models that can translate into changes that really improve patient care. It’s hard to make this happen without asking people who are affected most what would address their needs.”

That’s why Shelef and Dr. Teach’s most recent study, featured on the cover of the December 2016 issue of The Journal of Allergy and Clinical Immunology, shifts the research paradigm from a scientist-centered model to what they call a stakeholder-centered approach. Rather than develop the study solely with fellow researchers, the research team led by Children’s National relied heavily on guidance from people who would be most impacted by the results.

The study focused on whether an intervention that reduced parental stress could improve asthma outcomes among low-income African American children. To help design their study, the research team looked to several different sources for advice: African American parents of children treated for asthma at Children’s National; local providers of social, medical, legal and educational services; and experts in psychosocial stress, medication adherence and conducting studies among at-risk youth with asthma.

The researchers gave themselves one year to consult multiple times with each stakeholder group before starting to enroll study subjects in May 2015. In the initial planning phases, the research team intended to focus their study on whether reducing parental stress would change how well children stuck to taking their asthma medications. However, that focus quickly changed, says Shelef. “Medication adherence just wasn’t a meaningful goal to most parents,” she explains. “To them, having more symptom-free days was a better gauge of how well an intervention was working for their children.”

The proposed intervention itself also transformed. Rather than focusing on problem-solving, cognitive-reframing and parenting skills — the researchers’ initial ideas — the final intervention would instead teach participants mindfulness, deep breathing, positive thinking, self-care and gratitude — as well as how to use these coping skills with their children. Rather than being staffed by social workers or psychologists, the stakeholders preferred people they felt they could relate to: Community wellness coaches with experience teaching yoga, meditation or other wellness activities in neighborhoods in which they lived.

Several other tweaks significantly changed the study from its early incarnation into the final version that the researchers are currently implementing, says Dr. Teach. “We ended up in a very different place from where we started based on this extensive process of stakeholder engagement,” he says.

Shelef notes that it’s not always feasible to involve stakeholders so heavily or to intensively plan a study for a year before it begins. Keeping all the advisers focused on the study at hand without radically changing the focus was a challenge, she says, and it was an “incredible scramble” in the end to translate all of their feedback into a cohesive product. However, having input from the people who could gain the most from the research results made it all worth it.

“The real benefit to this approach is the richness of the final product,” Shelef says. “Ultimately, this study will show a lot more than if we hadn’t put so much into it at the beginning.”

Improving asthma care at community emergency departments

Through partnerships with community health care facilities, children suffering from severe asthma attacks can receive the type of state-of-the-art care championed by Children’s National.

Asthma is an exceedingly common pediatric disease, affecting nearly 7 million children in the United States, particularly in urban areas. Asthma is responsible for more than 775,000 Emergency Department (EDs) visits each year. However, the vast majority of these visits are to community EDs closest to patients’ homes, rather than to medical centers that specialize in pediatric care.

This fact could potentially lead to big problems for small patients, says Theresa A. Walls, M.D., M.P.H., Director of Emergency Department Outreach at Children’s National Health System. Nearly 70 percent of EDs in the United States treat fewer than 14 children a day, leaving many without the requisite experience or resources critical to effectively treat pediatric patients. Research shows that children seen for asthma in general community EDs are less likely to receive corticosteroid medications systemically — an essential first-line therapy during an asthma attack per National Institutes of Health guidelines — compared with children seen at pediatric EDs. Additionally in these general EDs, children are also more likely to receive unnecessary testing and treatment.

“In our experience, the emergency care of children with asthma in our area mirrors what has been found in national studies: Children are not treated as aggressively in community EDs. If we partner with them and get them to treat asthma as aggressively as we do, it would be a great thing for pediatric patients.”

That’s why when a nurse educator from a local community hospital’s ED contacted them to try to improve pediatric asthma care, Dr. Walls and Children’s colleagues jumped at the opportunity. “They were motivated participants,” she says. “It was a great way to start a partnership.”

The team worked with the community hospital’s ED to implement a pediatric asthma care plan known as a “pathway,” similar to the one currently in place at Children’s National, to ensure that children in the throes of an asthma attack receive evidence-based care that significantly decreases their chances of hospital admission or transfer to a specialty center.

The treatment pathway includes elements such as assigning each patient an asthma score — a number ranging from 1 to 10 that characterizes the severity of the patient’s asthma attack. The treatment plan also includes providing corticosteroids as quickly as possible to more eligible patients.

Effectively implementing this plan requires the efforts of a multidisciplinary team of providers and experts. Beyond the physicians, nurses and respiratory therapists who care for patients directly, this includes pharmacists to ensure proper doses of medications are available in child-friendly liquid forms and information technology specialists to revamp the hospital’s electronic charting system, automatically requesting an asthma score or recommending appropriate medication orders.

To gauge whether mimicking Children’s asthma pathway made a significant difference at the community ED, Dr. Walls and colleagues launched a study that was published online December 8, 2016, in Pediatrics. Comparing data collected for 19 months after the new guidelines were put into place with data from 12 months prior, the researchers made some promising initial findings. Following the pathway implementation, 64 percent of children ages 2 to 17 who arrived at the community ED with asthma symptoms received an asthma score. About 76 percent of these patients with asthma received corticosteroids after the pathway was in place, compared with 60 percent of comparable patients prior to the switchover. The mean time to corticosteroid administration dropped by nearly half, falling from 196 to 105 minutes. Additionally, Dr. Walls says, 10 percent of patients required transfer to another hospital after pathway implementation, compared with 14 percent before — another significant drop.

Dr. Walls notes that there is significant room for improving these metrics and overall asthma care at community EDs. The research team hopes to continue working with the first community hospital and expand their partnership to form a network of other local hospitals. By working together in a large collaboration, she says, hospitals can share resources and knowledge while learning from each other’s successes and mistakes.

“The more we can deliver this state-of-the-art care to the community,” she says, “the better, because that’s where most kids go.”

Children’s National spin-off ReveraGen announces agreement with actelion for Duchenne Muscular Dystrophy treatment

Earlier this month, ReveraGen BioPharma announced an exclusive option agreement with Actelion Ltd for lead compound vamorolone, a non-hormonal steroid modulator that is primarily used for the treatment of Duchenne Muscular Dystrophy (DMD). ReveraGen, the first Children’s National private spin-off company, is engaged in the discovery and development of proprietary therapeutic products for neuromuscular and inflammatory diseases.

Under the terms of the license agreement, Actelion and ReveraGen will partner to research and co-develop the novel compound vamorolone, which holds the potential to preserve muscle function and prolong ambulation in DMD patients, without some of the side effects that are commonly associated with glucocorticoid therapy. Those commonly associated include growth stunting and immune suppression, which can pose significant challenges for very young patients.

ReveraGen completed Phase I clinical trials for vamorolone in late 2015, and a Phase IIa program is currently underway to investigate the safety and efficiency of vamorolone in male DMD patients between four and seven years of age who have not taken deflazacort or prednisone. A Phase IIb program is also in early planning stages.

ReveraGen Co-Founder and CEO Eric Hoffman, PhD, has worked on DMD since the late 1980’s and has led his own research group for nearly 20 years at Children’s National. He co-founded ReveraGen back in 2008 with John McCall, PhD and Kanneboyina Nagaraju, PhD, DVM, before being named CEO in 2014. Children’s National maintains a 38 percent stake in ReveraGen.

Study reveals asthma phenotypes in inner-city children

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What’s known

According to the Centers for Disease Control and Prevention, 8.6 percent of children across the nation, or 6.3 million kids, have asthma, a disease characterized by wheezing and coughing associated with airway obstruction, bronchial hyperresponsiveness, and inflammation of the airway. However, children with asthma with low socioeconomic status who live in inner cities experience a disproportionately high burden of illness. While treatment guidelines provide uniformity in managing allergy and allergic inflammation, such approaches may be misdirected when kids have asthma symptoms but lack allergy or allergic inflammation. Knowledge of distinct disease phenotypes can help to improve care.

What’s new

The Asthma Phenotypes in the Inner City study enrolled school-aged kids living in nine U.S. inner cities, including Washington, DC. The research team collected data about their asthma at the beginning of the one-year study and every two months as the kids’ asthma was managed according to accepted guidelines. Phenotypic analysis for 616 of these kids found their asthma clustered into five distinct groups. Cluster “A” was characterized by lower allergy, lower inflammation, and minimal symptoms. Fifteen percent of the kids fit within “A.” Another 15 percent of kids’ asthma fit within Cluster “B.” They had highly symptomatic asthma despite high step-level treatment and relatively low allergy and inflammation. Cluster “C” was distinguished by minimal symptoms, intermediate allergy and inflammation, and mildly impaired pulmonary physiology. Some 24 percent of kids fit within this group. The remaining kids fit within Cluster “D” or “E” and experienced progressively higher asthma and rhinitis symptoms as well as allergy and inflammation.

Questions for future research

Q: How does exposure to allergens, viruses, and irritants like tobacco smoke—taken individually as well as in combination—influence asthma severity and symptoms for these at-risk youths?
Q: What approaches to treatment might result from these studies?

Training developing immune systems to prevent wheezing early in life

Stephen Teach does an asthma exam

Extensively engaging stakeholders such as parents, families and local service providers in the actual study design transformed a planned research project into a more patient-centered study.

For the small number of U.S. children who grow up on working farms, activities such as feeding the cows and clearing spent hay from the barn are little changed from a thousand years ago. Through such close contact with dirt and farm animals, rural kids’ immune systems develop more normally and better distinguish common bacteria from household allergens like dust, molds, pets, and pests. Rates of allergy and asthma continue to be lower in children who grow up in those conditions.

By contrast, rates of asthma have spiked among urban and disadvantaged kids, who have far less exposure to dirt and animals early in life. Today, leading pediatric institutions, such as Children’s National Health System, are “awash in emergency department (ED) visits for asthma” with each ED visit associated with 10 to 15 missed school days annually on a population basis, says Stephen J. Teach, MD, MPH, Director and Principal Investigator of IMPACT DC , a care, research, and advocacy program focused on under-resourced and largely minority children with asthma.

A paradigm-shifting multicenter clinical trial aims to reverse that trend by going old school and safely exposing very young infants to the type of immune system training they would have experienced if they grew up closer to the earth.

The five-year study, named “Oral Bacterial Extracts (ORBEX): Primary Prevention of Asthma and Wheezing in Children,” is funded by a $27 million cooperative agreement grant from the National Heart, Lung, and Blood Institute, which is part of the National Institutes of Health. Children’s National, one of eight participating sites across the nation, will enroll an estimated 150 children in the study and will receive at least $2.5 million of that grant.

“It is currently thought by many, including me, that asthma and allergic diseases are a result of disordered development of the immune system very early in life,” says Dr. Teach, who is also Chair of the Department of Pediatrics at George Washington University. The immune system development process begins to unfold in the last few months of pregnancy and continues through infancy, meaning “the die is cast, we think, at a very young age.”

According to the Centers for Disease Control and Prevention, 8.6 percent of children across the nation have asthma, but in the District of Columbia, a disproportionately higher number of children suffer from the respiratory ailment. Once children experience early wheezing, changes begin to occur in the architecture of their lungs, causing a thicker basement membrane, a thickening of the lining of the lungs, and resulting in a heightened tendency for the airways in the lungs to become inflamed and to excrete more mucous. As a result, the children’s poorly trained immune system becomes hyper vigilant, ready to recognize a multitude of things as potentially allergenic.

“We’ve got to do something to change the course of the disease and to make it less common and less severe,” Dr. Teach says.

The study will identify 1,000 babies who range in age from 6 months to 18 months who are the highest risk for asthma, either through family history, being diagnosed with eczema, or both. The infants will receive safe doses of the inactivated bacteria, which is marketed under the name Broncho-Vaxom®. The therapy comes in capsule form, which for two years will be sprinkled into bottles or onto food. The children will be followed to gauge whether infants randomly assigned to receive treatment suffer fewer respiratory symptoms than infants randomly assigned to receive placebo.

“The rationale if we can expose these very young children to the benefits, but not the risks, of early life bacterial exposure, they may reap the benefits of developing a more properly functioning and less allergic immune system,” Dr. Teach says.

He says the Children’s National research team has had “remarkable success” engaging young children and their parents in such long-term studies, losing few to attrition.

“Going for five years will be breaking new ground. But all of our experience suggests that we will succeed if we show the families we care, we stay in touch with them, and we form these therapeutic partnerships by saying: ‘We want to partner with you. We can do this safely with mutual benefit.’ Families will get on board,” he says.

Related resources: Learn more about the clinical trial | Research at a Glance

Training kids developing immune systems to prevent wheezing

PDF Version

What’s Known
Some 6.3 million U.S. children younger than 18—or 8.6 percent of the nation’s kids—have asthma. The disease is characterized by an inflammation of the airways, and    symptoms may be triggered by breathing in such allergens as animal dander, pollen, dust, or mold.

Once children experience early wheezing, changes begin in the architecture of their lungs, causing a thicker basement membrane, a thickening of the lining of the lungs, which can result in a heightened tendency for the airways in the lungs to become inflamed.

What’s New
Asthma and allergic diseases are thought to result from disordered development of the immune system, a process that begins in the womb. A paradigm-shifting multicenter clinical trial will enroll patients at eight locations, including Children’s National Health System, to provide the type of “immune system training” that infants would experience if they grew up in rural settings—where most children’s immune systems develop more normally. The five-year study funded by the National Heart, Lung, and Blood Institute will identify 1,000 babies aged 6 months to 18 months who are at risk for asthma to receive safe doses of an inactivated bacteria to help them develop more properly functioning immune systems. The University of Arizona Health Sciences in Tucson will lead the national research effort. Researchers will gauge whether infants randomly assigned to receive treatment suffer fewer respiratory symptoms than infants randomly assigned to receive placebo.

Questions for Future Research
Q: What will be the longer-term effects of preventing early wheezing? Will the children develop asthma less frequently?
Q: If intervention with young children occurs early enough to interrupt the disease cycle—preventing asthma, wheezing, and allergies—will they miss fewer days of school when they are older?
Q: Will families be willing to consistently follow the complex regimen necessary to administer the inactivated bacterial products on a long-term basis?

Source: Oral Bacterial Extracts (ORBEX): Primary Prevention of Asthma and Wheezing in Children.

Enroll in this clinical trial—https://clinicaltrials.gov/ct2/show/NCT02148796

Allergy and immunology update: asthma care, microbial signatures

June 16, 2016 – Increased identification of the primary care provider as the main source of asthma care among urban minority children
The research team used electronic communication between an asthma specialty clinic and short-term care coordination to encourage parents of urban youth with asthma to identify their primary care provider as the key source for episodic asthma care – rather than the emergency department. Guardians of 50 children were enrolled in the prospective cohort study, whose findings were published in Journal of Asthma. The youths’ median age was 5.8 years; 64 percent were male, 98 percent were African American. At three and six months after the intervention, 85 percent and 83 percent, respectively, reported that the primary care provider was their child’s primary asthma healthcare provider, compared with 70 percent at baseline. 

June 16, 2016 – Two sampling methods yield distinct microbial signatures in the nasopharynges of asthmatic children
The nasopharynx acts as an anatomical reservoir from which pathogenic microbes spread to the lower and upper respiratory airways, causing respiratory infections. A team led by Children’s National researchers used targeted 16S rRNA MiSeq sequencing and two techniques – nasal washes and nasal brushes – to characterize the nasopharyngeal microbiota in 30 children with asthma aged 6 to 17. The authors report in Microbiome that the children’s nasopharyngeal microenvironments contain microbiotas with different diversity and structure.

Nov. 30, 2015 – Alex’s Lemonade Stand Foundation grant to develop immune-based therapy
Physician-scientist Conrad Russell Y. Cruz, MD, PhD, was awarded a $450,000, grant from the Alex’s Lemonade Stand Foundation to develop novel cell-based therapies to combat pediatric cancer. The “A” grant encourages scientists to develop innovative treatments and cures that impact children with cancer and will provide Dr. Cruz and his team funding for three years.