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coronavirus

Higher COVID-19 rates seen in minority socioeconomically disadvantaged children

coronavirus

Minority and socioeconomically disadvantaged children have significantly higher rates of COVID-19 infection, a new study led by Children’s National Hospital researchers shows.

Minority and socioeconomically disadvantaged children have significantly higher rates of COVID-19 infection, a new study led by Children’s National Hospital researchers shows. These findings, reported online August 5 in Pediatrics, parallel similar health disparities for the novel coronavirus that have been found in adults, the authors state.

COVID-19, an infection caused by the novel coronavirus SARS-CoV-2 that emerged in late 2019, has infected more than 4.5 million Americans, including tens of thousands of children. Early in the pandemic, studies highlighted significant disparities in the rates of infection in the U.S., with minorities and socioeconomically disadvantaged adults bearing much higher burdens of infection. However, says Monika Goyal, M.D., M.S.C.E, a pediatric emergency medicine specialist and associate division chief in the Division of Emergency Medicine at Children’s National whose research focuses on health disparities, it’s been unclear whether these disproportionate rates of infection also extend to youth.

To investigate this question, she and her colleagues looked to data collected between March 21, 2020, and April 28, 2020, from a drive-through/walk-up COVID-19 testing site affiliated with Children’s National — one of the first exclusively pediatric testing sites for the virus in the U.S. To access this free testing site, funded by philanthropic support, patients between the ages of 0 and 22 years needed to meet specific criteria: mild symptoms and either known exposure, high-risk status, family member with high-risk status or required testing for work. Physicians referred patients through an online portal that collected basic demographic information, reported symptoms and the reason for referral.

When Dr. Goyal and her colleagues analyzed the data from the first 1,000 patients tested at this site, they found that infection rates differed dramatically among different racial and ethnic groups. While about 7% of non-Hispanic white children were positive for COVID-19, about 30% of non-Hispanic Black and 46% of Hispanic children were positive.

“You’re going from about one in 10 non-Hispanic white children to one in three non-Hispanic Black children and one in two Hispanic children. It’s striking,” says Dr. Goyal.

Using data from the American Families Survey, which uses five-year census estimates derived from home address to estimate median family income, the researchers separated the group of 1,000 patients into estimated family income quartiles. They found marked disparities in COVID-19 positivity rates by income levels: while those in the highest quartile had infection rates of about 9%, about 38% of those in the lowest quartile were infected.

There were additional disparities in exposure status, Dr. Goyal adds. Of the 10% of patients who reported known exposure to COVID-19, about 11% of these were non-Hispanic white. However, non-Hispanic Black children were triple this number.

Although these numbers show clear disparities in COVID-19 infection rates, the authors are now trying to understand why these disparities occur and how they can be mitigated.

“Some possible reasons may be socioeconomic factors that increase exposure, differences in access to health care and resources, as well as structural racism,” says Dr. Goyal.

She adds that Children’s National is working to address those factors that might increase risk for COVID-19 infection and poor outcomes by helping to identify unmet needs — such as food and/or housing insecurity — and steer patients toward resources when patients receive their test results.

“As clinicians and researchers at Children’s National, we pride ourselves on not only being a top-tier research institution that provides cutting-edge care to children, but by being a hospital that cares about the community we serve,” says Denice Cora-Bramble, M.D., M.B.A., chief medical officer of Ambulatory and Community Health Services at Children’s National and the research study’s senior author. “There’s still so much work to be done to achieve health equity for children.”

Other Children’s National researchers who contributed to this study include Joelle N. Simpson, M.D.; Meleah D. Boyle, M.P.H, Gia M. Badolato, M.P.H; Meghan Delaney, D.O,. M.P.H.; and Robert McCarter Jr., Sc.D.

mother measuring sick child's temperature

Connections between Kawasaki disease and MIS-C

mother measuring sick child's temperature

A new review article enumerates some key similarities and differences between MIS-C and Kawasaki disease.

Since May 2020, there has been some attention in the general public and the news media to a specific constellation of symptoms seen in children with COVID-19 or who have been exposed to COVID-19. For a time, headlines even called it a “Kawasaki-like” disease. At first glance, both the symptoms and the effective treatments are remarkably similar. However, a new review published in Trends in Cardiovascular Medicine finds that under closer scrutiny, the two conditions have some interesting differences as well.

“At the beginning of this journey, we thought we might be missing actual cases of Kawasaki disease because we identified a few patients who presented late and developed coronary artery abnormalities,” says Ashraf Harahsheh, M.D., senior author of the review article, “Multisystem inflammatory syndrome in children: Is there a linkage to Kawasaki disease?” and a cardiologist at Children’s National Hospital. “But as time passed, children exposed to COVID-19 started to present with a particular constellation of symptoms that actually had some important similarities and distinctions from Kawasaki.”

Similarities between Kawasaki disease and MIS-C

Both disease patterns seem to have a common trigger that provokes the inflammatory cascade reaction in genetically susceptible children, the authors write. However, there is also early evidence that children with each disease have different genetic markers, meaning different populations are genetically susceptible to each disease.

Additionally, the authors found that the massive activation of pro-inflammatory cytokines seen in MIS-C, also known as a “cytokine storm,” overlaps with a similar occurrence seen in Kawasaki disease, adult COVID-19 patients, toxic shock syndrome and some other viral infections.

Primary differences between Kawasaki disease and MIS-C

Overall, when compared to Kawasaki disease, children with MIS-C tend to:

  • Present at an older age
  • Have a more profound form of inflammation
  • Have more gastrointestinal manifestation
  • Show different laboratory findings
  • Have greater risk of left ventricle dysfunction and shock

Further study of both Kawasaki and MIS-C needed

Despite noted differences, the authors are also careful to credit the documented similarities between Kawasaki disease and MIS-C as a key to the quick identification of the new syndrome in children. The study of Kawasaki disease also gave clinicians a valid basis to begin developing diagnostic recommendations and treatment protocols.

The review’s first author Yue-Hin Loke, M.D., who is also a cardiologist at Children’s National, says, “The quick recognition of MIS-C is only possible because of meticulous research conducted by Dr. Tomisaku Kawasaki, who recently passed away on June 5th, 2020. Even though some aspects of both are still shrouded in mystery, the previous research and clinical advancements made in Kawasaki disease set the stage for our immediate response to MIS-C.”

“Previous research provided key information for cardiologists facing this new syndrome, including the necessity of routine echocardiograms to watch for coronary artery abnormalities (CAAs) and for use of  intravenous immunoglobulin (IVIG) to mitigate  the development of CAAs,” says Charles Berul, M.D., chief of Cardiology at Children’s National and a co-author. “Both of these factors have played a key role in reducing the mortality of MIS-C to almost zero.”

The authors note that more research is needed to understand both Kawasaki disease and the specifics of MIS-C, but that what is learned about the mechanisms of one can and should inform study and treatment of the other. And in the meantime, caution and continued surveillance of these patients, especially with respect to coronary artery and myocardial function, will continue to improve the long-term outcomes for both syndromes.

Yuan Zhu

Study suggests glioblastoma tumors originate far from resulting tumors

Yuan Zhu

“The more we continue to learn about glioblastoma,” Yuan Zhu, Ph.D., says, “the more hope we can give to these patients who currently have few effective options.”

A pre-clinical model of glioblastoma, an aggressive type of cancer that can occur in the brain, suggests that this recalcitrant cancer originates from a pool of stem cells that can be a significant distance away from the resulting tumors. The findings of a new study, led by Children’s National Hospital researchers and published July 22 in the journal Nature Communications, suggest new ways to fight this deadly disease.

Despite decades of research, glioblastoma remains the most common and lethal primary brain tumor in adults, with a median survival of only 15 months from diagnosis, says study leader Yuan Zhu, Ph.D., the scientific director and endowed professor of the Gilbert Family Neurofibromatosis Institute at Children’s National. Unlike many cancers, which start out as low-grade tumors that are more treatable when they’re caught at an early stage, most glioblastomas are almost universally discovered as high-grade and aggressive lesions that are difficult to treat with the currently available modalities, including surgery, radiation and chemotherapy.

“Once the patient has neurological symptoms like headache, nausea, and vomiting, the tumor is already at an end state, and disease progression is very rapid,” Dr. Zhu says. “We know that the earlier you catch and treat cancers, the better the prognosis will be. But here, there’s no way to catch the disease early.”

However, some recent research in glioblastoma patients shows that the subventricular zone (SVZ) – an area that serves as the largest source of stem cells in the adult brain – contains cells with cancer-driving mutations that are shared with tumors found in other often far-distant brain regions.

To see if the SVZ might be the source for glioblastoma tumors, Dr. Zhu and his colleagues worked with pre-clinical models that carried a single genetic glitch: a mutation in a gene known as p53 that typically suppresses tumors. Mutations in p53 are known to be involved in glioblastoma and many other forms of cancer.

Using genetic tests and an approach akin to those used to study evolution, the researchers traced the cells that spurred both kinds of tumors back to the SVZ. Although both single and multiple tumors had spontaneously acquired mutations in a gene called Pten, another type of tumor suppressor, precursor cells for the single tumors appeared to acquire this mutation before they left the SVZ, while precursor cells for the multiple tumors developed this mutation after they left the stem cell niche. When the researchers genetically altered the animals to shut down the molecular pathway that loss of Pten activates, it didn’t stop cancer cells from forming. However, rather than migrate to distal areas of the brain, these malignant cells remained in the SVZ.

Dr. Zhu notes that these findings could help explain why glioblastoma is so difficult to identify the early precursor lesions and treat. This work may offer potential new options for attacking this cancer. If new glioblastoma tumors are seeded by cells from a repository in the SVZ, he explains, attacking those tumors won’t be enough to eradicate the cancer. Instead, new treatments might focus on this stem cell niche as target for treatment or even a zone for surveillance to prevent glioblastoma from developing in the first place.

Another option might be to silence the Pten-suppressed pathway through drugs, a strategy that’s currently being explored in various clinical trials. Although these agents haven’t shown yet that they can stop or reverse glioblastomas, they might be used to contain cancers in the SVZ as this strategy did in the pre-clinical model — a single location that might be easier to attack than tumors in multiple locations.

“The more we continue to learn about glioblastoma,” Dr. Zhu says, “the more hope we can give to these patients who currently have few effective options.”

Other Children’s National researchers who contributed to this study include Yinghua Li, Ph.D., Wei Li, Ph.D., Yuan Wang, Ph.D., Seckin Akgul, Ph.D., Daniel M. Treisman, Ph.D., Brianna R. Pierce, B.S., Cheng-Ying Ho, M.D. /Ph.D.

This work is supported by grants from the National Institutes of Health (2P01 CA085878-10A1, 1R01 NS053900 and R35CA197701).

screenshot of pitch competition

“COVID-19-edition” of pediatric medical device competition announces winners

$1M grant funds research on quantitative imaging for tumors

“For children who are at risk of losing their vision, this project will bring a window of opportunity for physicians to start treatment earlier and save their vision,” says Marius George Linguraru, DPhil, MA, MSc.

A team from Children’s National Hospital is part of a project receiving a two-year grant of nearly $1,000,000 from the National Institutes of Health (NIH) for the first pediatric project in the Quantitative Imaging Network (QIN) of the National Cancer Institute (NCI). Marius George Linguraru, DPhil, MA, MSc, principal investigator from the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Hospital in Washington, D.C., is one of two principal investigators on the project, which focuses on developing quantitative imaging (QI) tools to improve pediatric tumor measurement, risk predictions and treatment response. Roger Packer, M.D., Senior Vice President of the Center for Neuroscience & Behavioral Health, Director of the Gilbert Neurofibromatosis Institute and Director of the Brain Tumor Institute, is co-investigator.

The project, in collaboration with Children’s Hospital of Philadelphia and Children’s Hospital Colorado, centers on the most common type of brain tumor in children, called a low-grade glioma. This project focuses on a clinically challenging group of children with neurofibromatosis type 1 (NF1), the most common inherited tumor predisposition syndrome. Nearly 20% of children with NF1 will develop a low-grade glioma called optic pathway glioma (OPG). In children with this type of brain tumor, the growth occurs around the optic nerve, chiasm and tracts, also called the optic pathway, which connects the eye to the brain. OPGs can cause vision loss and even blindness. Permanent vision loss usually occurs between one and eight years of age with doctors closely monitoring the tumor with magnetic resonance imaging (MRI) to assess the disease progression.

“Our traditional two-dimensional measures of tumor size are not appropriate to assess the changes in these amorphous tumors over time or how the tumor responds to treatment,” says Linguraru. “This means physicians have difficulty determining the size of the tumor as well as when treatment is working. Research such as this can lead to innovative medical technologies that can improve and possibly change the fate of children’s lives.”

Dr. Linguraru is leading the technical trials on this project, which take place in the first two years, or phase one, starting in June 2020. Phase one focuses on improving the often inaccurate human measurements of tumor size by developing QI tools to make precise and automated measures of tumor volume and shape using machine learning. In this phase, the project will use and homogenize MRI data from multiple centers to develop predictive models of the treatment response based on the tumor volume that are agnostic to the differences in imaging protocols. By doing this, it will allow physicians to make more informed decisions about the treatment’s success and whether the child will recover their vision.

When phase one is complete, Linguraru and the project’s other principal investigator Robert A. Avery, DO, MSCE, neuro-ophthalmologist in the Division of Ophthalmology at Children’s Hospital of Philadelphia, will initiate the second phase, which includes validating the QI application on data from the first ever phase III clinical trial comparing two treatments for NF1-OPGs. Phase two is scheduled to start in the Summer 2022 and continue through Summer 2025.

“For children who are at risk of losing their vision, this project will bring a window of opportunity for physicians to start treatment earlier and save their vision,” says Linguraru. “For those children who won’t benefit from chemotherapy because the tumor poses no threat to their sight, this project will save them from having to go through that difficult treatment unnecessarily. It will be life-changing for the children and their families, which is what excites me about this QI application.”

This project is a collaboration between Children’s Hospital of Philadelphia and Children’s National Hospital in Washington, D.C., in partnership with Children’s Hospital of Colorado and University of Pennsylvania. Upon project completion, the QI application will provide a precision-medicine approach for NF1-OPGs and improve clinical outcomes for pediatric tumors.

NCC-PDI-COVID19-Edition-Competition

“COVID-19-edition” of pediatric medical device competition announces finalists

Sixteen finalists have been selected in the “Make Your Medical Device Pitch for Kids!” special COVID-19 edition competition presented by the National Capital Consortium for Pediatric Device Innovation (NCC-PDI). Representing innovations in COVID-19-related pediatric medical devices, the finalists will compete in a virtual pitch event held on July 20,2020 where up to $250,000 in awards will be given. Winners will receive grant funding of up to $50,000.

The competition is led by NCC-PDI co-founders the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Hospital and the A. James Clark School of Engineering at the University of Maryland and powered by nonprofit accelerator and NCC-PDI member, MedTech Innovator.

This competition focuses on pediatric medical devices that support home health monitoring and telehealth, and improve sustainability, resiliency and readiness in diagnosing and treating children during a pandemic.

“As COVID -19 continues to threaten the health of families and children across the nation, we must continue to seek new and better ways to deliver quality care during a pandemic and offer technology solutions to reopen more safely,” says Kolaleh Eskandanian, Ph.D., MBA, PMP, vice president and chief innovation officer at Children’s National Hospital and principal investigator of NCC-PDI. “Competitions like this are vital to get ahead of the healthcare challenge that COVID-19 presents in the world of pediatrics. By supporting innovation, we provide critical breakthroughs that can positively impact the lives of the children and families we serve.”

Along with grant funding, one company from the competition will be selected by Johnson & Johnson Innovation – JLABS to receive a one-year residency at JLABS @ Washington, DC, which will be located on the new Children’s National Research & Innovation Campus currently under construction. In addition to the 2021 JLABS residency, the awardee will have access to the JLABS community and expert mentoring by the Johnson & Johnson family of companies.

The 16 pediatric device innovations that judges selected for the final competition include:

  • Adipomics – simple and fast, one-step COVID-19 diagnostic kit for home or school use
  • Bloom Standard (Kaaria) – wearable, AI-driven ultrasound for infant cardiac and pulmonary screening and diagnostics
  • CereVu Medical – remote COVID-19 sensor, monitor and centralized data hub that measures blood oxygen saturation, muscle aches, temperature and trouble breathing
  • Children’s Hospital of Philadelphia – a transparent reusable DIY origami facemask that reveals facial expressions & improves communication
  • Children’s National Hospital – Lab-on-a-chip device for high-throughput combination drug screening
  • Hopscotch – gamified cognitive behavioral therapy-based computer exercises to encourage kids to stay engaged and complete treatment programs
  • Medichain – cost effective, accurate COVID-19 test with results in minutes and can detect the virus in the early stage
  • Medipines – monitor device that displays critical respiratory parameters analyzed from a patient’s breathing sample
  • OtoPhoto – a smart otoscope that quickly and accurately aids diagnosis of ear infections for home telehealth use
  • OxiWear – continuous wear oxygen-monitoring device used to reduce patient insecurity
  • REALTROMINS – real time, continuously updated predictive analytics to identify impending mortality in children
  • SurgiPals – digital assistant and urine biochemical sensor to aid in outpatient care of children with COVID-19
  • TGV-Dx – a novel, phenotype-based test system for rapid selection of effective antibiotic regimen
  • VitaScope – quick, accurate infant vital signs to facilitate high-quality virtual care
  • Vitls – wearable platform for remote patient monitoring of the vitals clinicians require to assess a patient
  • X-Biomedical – rugged, portable smart ICU ventilator for pediatric and adult patients

Funding for the competition is made possible by a grant from the Food and Drug Administration (FDA) and a philanthropic gift from Mei Xu, founder of e-commerce platform Yes She May, a site dedicated to women-owned brands.

In addition to this COVID-19 special edition event, NCC-PDI recently revealed the ten finalists in its prestigious 8th annual “Make Your Medical Device Pitch for Kids!” competition. Cardiovascular, NICU, and orthopaedic and spine device innovations are the focus of the fall competition, taking place October 7, 2020 as part of the 8th Annual Symposium on Pediatric Device Innovation, presented by Children’s National and co-located with The MedTech Conference powered by AdvaMed.

pitch competition finalists

zika virus

The importance of following the Zika population long-term

zika virus

Invited commentary by Sarah Mulkey, M.D., Ph.D., prenatal-neonatal neurologist in the Division of Prenatal Pediatrics at Children’s National Hospital, emphasizes importance of studying the Zika population long term.

A simple measuring tape could be the key to identifying which children could develop neurological and developmental abnormalities from Zika virus exposure during gestation. This is according to an invited commentary published July 7, 2020 in JAMA Network Open and written by Sarah Mulkey, M.D., Ph.D., prenatal-neonatal neurologist in the Division of Prenatal Pediatrics at Children’s National Hospital.

Zika virus (ZIKV), first isolated in 1947 in the Ziika Forest in Uganda, made headlines in 2015-2016 for causing a widespread epidemic that spread through parts of North and South America, several islands in the Pacific and parts of Southeast Asia. Although previously linked with no or mild symptoms, researchers discovered during this epidemic that Zika can cross from a pregnant woman to her gestating fetus, leading to a syndrome marked by microcephaly (decreased brain growth), abnormal neurologic tone, vision and hearing abnormalities and joint contractures.

“For the 90% to 95% of ZIKV-exposed infants who fortunately were not born with severe abnormalities at birth and were normocephalic, our hope was that these children would have normal neurodevelopmental outcomes,” Dr. Mulkey writes in the commentary. “Unfortunately, this has not been the case.”

Her commentary expands on a study in the same issue entitled “Association between exposure to antenatal Zika virus and anatomic and neurodevelopmental abnormalities in children” by Cranston et al. In this study, the researchers find that head circumference — a simple measure taken regularly at postnatal appointments in the U.S. — can provide insight into which children were most likely to develop neurologic abnormalities. Their findings show that 68% of those whose head circumference was in the “normal” range at birth developed neurologic problems. Those whose head circumference was at the upper end of this range were significantly less likely to have abnormalities than those at the lower end.

Just this single measurement offers considerable insight into the risk of developing neurologic problems after Zika exposure. However, notes Dr. Mulkey, head circumference growth trajectory is also key. Of the 162 infants whose heads were initially in the normocephalic range at birth, about 10.5% went on to develop microcephaly in the months after birth.

“Because early head growth trajectory is associated with cognitive outcomes in early childhood,” Dr. Mulkey writes, “following the head circumference percentile over time can enable recognition of a child with increased risk for poor outcome who could benefit from early intervention therapies.”

This simple assessment could be significantly augmented with neuroimaging, she adds. The study by Cranston et al., as well as others in the field, have shown that brain imaging often reveals problems in ZIKV-exposed children, such as calcifications and cerebral atrophy, even in those with normal head circumferences. This imaging doesn’t necessarily need to take place at birth, Dr. Mulkey says. Postnatal development of microcephaly, failure to thrive or developmental delay can all be triggers for imaging later on.

Together, Dr. Mulkey says, the study by Cranston et al. and others that focus on ZIKV-exposed children support the need for following these patients long term. Children exposed to ZIKV in the epidemic nearly five years ago are now approaching school age, a time fraught with more complicated cognitive and social demands. Through her own research at Children’s National’s Congenital Zika Virus Program and collaboration with colleagues in Colombia, Dr. Mulkey is following multiple cohorts of ZIKV exposed children as they grow. She recently published a study on neurological abnormalities in one of these cohorts in JAMA Pediatrics in January 2020.

“It’s really important to follow these children as long as possible so we’ll really know the outcomes of this virus,” Dr. Mulkey says.

Staphylococcus

Airway microbial diversity in children with Cystic Fibrosis

Staphylococcus

Despite having less overall microbial richness, children with Cystic Fibrosis displayed a greater presence of Staphylococcus species.

Cystic Fibrosis (CF) is a disease that mainly affects the lungs and arises from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes for the CFTR membrane protein located on certain secretory cells. CFTR dysfunction leads to complications such as the production of abnormally viscous mucus which causes chronic suppurative lung infections that require antibiotics to treat. New drugs called CFTR modulators can help improve CFTR protein function and some are even FDA-approved for use in children. In addition to CFTR protein function, the lung’s resident microbiota and its richness of diversity, plays an important role in both health and disease, including CF.

In a new study published in Heliyon, scientists from Children’s National Hospital examined the difference in the upper airway microbiome between children with CF and healthy controls. Age-related differences among children with CF and the impact of CFTR modulators on microbial diversity were also assessed. Seventy-five children between 0-6 years of age participated in the study, including 25 children with CF and 50 healthy controls. For CF participants, oropharyngeal swabs and clinical data were obtained from the biorepository, while data for controls were obtained during a single clinical visit.

Analysis revealed that CF patients had less microbial diversity and different composition of the upper airway microbiome compared to age similar controls, a finding that is consistent with research on the lower airways. Despite having less overall microbial richness, children with CF displayed a greater presence of Staphylococcus species, (a main driver of the pulmonary exacerbations characteristic of CF), three Rothia operational taxonomic units (OTUs) and two Streptococcus OTUs. CF patients received a significantly higher number of antibiotics courses within the previous year compared to healthy controls, and further investigation will be necessary to understand the impact of antibiotics on the upper airway microbiome of infants and children with CF.

Longitudinal comparisons to study effects of age and CFTR modulation on the microbiome of children with CF were also undertaken. Younger CF patients (those 0 to <3 years of age at study enrollment), were more likely to have culturally-normal respiratory flora and more stable microbial composition over time than older CF patients (those ≥ 3–6 years of age at study enrollment), with no significant differences in alpha or beta diversity. Older CF patients were significantly more likely to be receiving a CFTR modulator than younger patients. CF patients receiving CFTR modulators had higher microbial diversity measures than those not receiving CFTR modulators and were closer (but still significantly lower) in microbial richness to healthy controls. No significant differences in beta diversity were found between the three groups.

This study adds to the growing body of evidentiary support for the use of CFTR modulators in improving airway microbial diversity in CF patients. Future studies with a larger cohort and greater focus on the impact on early initiation of CFTR modulators on microbial diversity and clinical outcomes is necessary.

The study, “Airway microbial diversity is decreased in young children with cystic fibrosis compared to healthy controls but improved with CFTR modulation,” was recently published in Heliyon. The lead author is Andrea Hahn, M.D., M.S., an investigator at the Children’s National Research Institute. Notable authors include Aszia Burrell; Emily Ansusinha; Hollis Chaney, M.D.; Iman Sami, M.D.; Geovanny F. Perez, M.D.; Anastassios C. Koumbourlis, M.D., M.P.H.; Robert McCarter, Sc.D.; and Robert J. Freishtat, M.D., M.P.H..

Nobuyuki Ishibashi

R01 grant funds white matter protection study for congenital heart disease

Nobuyuki Ishibashi

Nobuyuki Ishibashi, M.D., is the principal investigator on a $3.2 million NIH R01 to study white matter growth and repair in utero for fetal brains affected by congenital heart disease.

Many of the neurological deficits seen in children with congenital heart disease (CHD) are related to abnormal white matter development early in life caused by reduced oxygen supply to the brain while in utero. Children with immature white matter at birth also commonly sustain additional white matter injuries following cardiac surgery.

The NIH recently awarded a prestigious R01 grant totaling more than $3.2 million to a collaborative project led by the Center for Neuroscience Research, the Sheikh Zayed Institute for Pediatric Surgical Innovation and the Children’s National Heart Institute at Children’s National Hospital as well as MedStar Washington Hospital Center.

The research, titled “White matter protection in the fetus with congenital heart disease,” looks specifically at whether providing a supplemental amount of the naturally occurring tetrahydrobiopterin (BH4) for pregnant women could rescue white matter development of fetuses with congenital heart disease whose brains aren’t receiving enough oxygen – or suffering from hypoxic-ischemic events.

Previous preclinical studies have shown that this lack of oxygen depletes the brain’s natural BH4 level, and the researchers hypothesize that BH4 levels play a critical role in the growth and development of white matter in the fetal brain by triggering key cellular/molecular processes. Specifically, the study will focus on three aims:

  1. Establish in a preclinical model the optimal protective regiment for women pregnant with a fetus who has CHD to receive BH4.
  2. Determine the appropriate approach to deliver BH4 to this population
  3. Leverage genetic tools and biochemical techniques in the laboratory to better understand where and how BH4 levels play a role in the growth (or lack thereof) of oligodendrocytes—the primary cells of white matter.

This laboratory-based work is the first step to determining if the neurodevelopment of babies born with CHD can be preserved or recovered by addressing key brain development that occurs before the baby is even born. Findings related to congenital heart disease may also translate to other populations where white matter development is affected by hypoxia-ischemia, including premature infants.

The project is led by principal investigator Nobuyuki Ishibashi, M.D., with co-investigators Vittorio Gallo, Ph.D., Joseph Scafidi, D.O., and Mary Donofrio, M.D. as well as colleagues at MedStar Washington Hospital Center.

child using inhaler

The search for new Cystic Fibrosis clinical biomarkers

child using inhaler

Physician-scientists from Children’s National Hospital are unlocking new insights into Cystic Fibrosis by studying the type and number of bacteria in the lungs.

Cystic Fibrosis (CF) is a genetic disorder that chiefly affects the lungs and results in the production of abnormally dehydrated, viscous mucus. The inability to adequately clear this mucus leads to bacterial retention and both intermittent and chronic lung infections which require antibiotic therapy to treat. Researchers have used 16S rDNA amplicon sequencing for years in the attempts to characterize the airway microbiomes of CF patients, and more recently have used shotgun whole genome sequencing (WGS) techniques to obtain further details regarding bacterial species and strains. Previous studies on the airway microbiomes of CF patients have revealed that inter-person variability is high and can sometimes exceed intra-person variability. This can preclude generalizations regarding the CF population as a whole, which includes more than 30,000 Americans.

A recently published case study examined a young child with advanced and severely aggressive CF over a 12-month period, during which five pulmonary exacerbations occurred. A total of 14 sputum samples were collected across three clinical periods- baseline, exacerbation, and treatment. Samples were subsequently genetically sequenced (via 16s rDNA sequencing and, in three instances, WGS) and volatile metabolites were analyzed. The researchers hypothesized that if signature microbiome and metabolome characteristics correlated with one other and could be identified for each disease state, this data could serve as conglomerate biomarkers for the continuum of CF clinical states within an individual. In turn, this could inform future study design in a larger cohort.

Across all sputum samples, 109 individual operational taxonomic units (OTUs) and 466 distinct volatile metabolites were identified. 16s rDNA sequencing and WGS revealed that Escherichia coli and Staphylococcus aureus were the predominant bacteria during most baseline and exacerbation samples, despite some significant fluctuations in relative abundances. After the patient’s fifth antibacterial course, however, Achromobacter xylosoxidans became the new dominant bacterium.

Analysis revealed that the phylum Bacteroidetes and the genus Stenotrophomonas were significantly more abundant in treatment periods compared to baseline and exacerbation periods. WGS revealed the presence of bacteriophages as well as antibiotic resistance genes (mostly due to multi-drug resistance mechanisms), which can have important clinical ramifications and adds some dimensionality to the genetic analysis.

Volatile metabolite analysis found that observable fluctuations in metabolome composition coincided with fluctuations in the sputum microbiome. In this case, the microbiome and volatile metabolites produced by these bacteria provided an accurate assessment of the child’s clinical state. More specifically, the authors saw a distinct shift in both the microbiome and volatile metabolites with antibiotic treatment across the five independent pulmonary exacerbations. These additional assessments of the bacteria within the CF airway could provide an additional technique beyond standard bacterial cultures to better understand how the patient is responding to antibiotic treatment. Future studies in a larger group of children with CF may provide further insights into bacteria and volatile metabolite combinations that predict pulmonary exacerbation.

The article, “Longitudinal Associations of the Cystic Fibrosis Airway Microbiome and Volatile Metabolites: A Case Study,” was published in Frontiers in Cellular and Infection Microbiology. The lead author is Andrea Hahn, M.D., M.S., an investigator at the Children’s National Research Institute. Notable authors include Iman Sami, M.D., pulmonologist at Children’s National; Anastassios C. Koumbourlis, M.D., M.P.H, director of the Cystic Fibrosis Center; and Robert J. Freishtat, M.D., M.P.H, senior investigator at the Center for Genetic Medicine Research.

doctor and patient filling out paperwork

How advance care planning can improve life in a pandemic and beyond

doctor and patient filling out paperwork

New research, published in AIDS and Behavior, shows the effectiveness of an Advance Care Planning model developed through participatory research with adolescents in improving palliative care among adult people living with HIV (PLWH).

Since the beginning of the COVID-19 pandemic, there has been a dramatic increase in advance care planning (ACP) and the creation of advance directives, also known as living wills, in the United States. New research, published in AIDS and Behavior, shows the effectiveness of an ACP model developed through participatory research with adolescents in improving palliative care among adult people living with HIV (PLWH).

These findings demonstrate that ACP positively contributes to the palliative care of adult PLWH by relieving suffering and maximizing quality of life. The intervention was based on the FAmily CEntered (FACE) Advance Care Model, which was developed and tested by principal investigator Maureen E. Lyon, Ph.D., and her colleagues.

Dr. Lyon’s team used this model successfully with adolescents living with HIV as part of five-year, five-site trial that included Children’s National Hospital. The trial was co-funded by the National Institutes of Health and National Institute of Nursing Research. The success of that study was parlayed into a new five-year study testing a slightly modified ACP intervention in adults, with Children’s National serving as the coordinating center. “The adolescents showed us the way,” says Dr. Lyon.

The paper details the findings of a longitudinal, two arm, randomized controlled clinical trial examining whether an ACP intervention aimed at adult PLWH and their families correlated with higher congruence in treatment preferences, as well as higher congruence over time. Patient-surrogate dyads were randomized to an ACP intervention arm or an active control arm at a 2:1 ratio (86 intervention dyads and 43 control dyads at 18-month follow up), due to prior demonstrated benefit of ACP.

The ACP intervention consisted of two 60-minute, patient-focused sessions. During session 1, Respecting Choices Next Steps® ACP Conversation, both patients and their surrogate decision-makers focused on the patients’ understanding of HIV, experience of symptoms, fears, hopes and worries. Next, a patient’s treatment preferences were explored via the Statement of Treatment Preferences (SoTP), which became a part of the patient’s electronic health record (EHR). Surrogates were questioned on their comprehension and willingness to comply with the patient’s wishes. Session 1 was acknowledged as the beginning of a conversation, and continued conversation between the dyad was encouraged.

Session 2, Five Wishes©, involved a facilitator guiding the dyad through a Five Wishes© advance directive. Session 2 resulted in legal documentation of a patient’s preferences in five specific areas: The patient’s preferred health care decision-maker, the kind of medical treatment the patient wants, how comfortable the patient wants to be, how the patient wants people to treat him/her and what the patient wants loved ones to know. The patient, surrogate and treating physicians all received a copy, and a copy was also submitted to the patient’s EHR.

Dyads in the control arm participated in two 60-minute sessions entitled Developmental or Relationship History (excluding any medical questions) and Nutrition & Exercise.

The researchers then assessed treatment preference congruence for each patient-surrogate dyad by presenting them with five different hypothetical scenarios. After the first session, congruence across all scenarios was significantly higher among ACP intervention dyads compared to control dyads. ACP patients were also significantly more likely to give their surrogates leeway in treatment decision making compared to control patients.

Compared to control dyads, ACP dyads were significantly more likely to maintain High → High congruence transition and significantly less likely to experience Low → Low congruence transition as measured from immediately post-intervention to 12-months post-intervention. The only two cases of Low → High congruence transition occurred in the intervention arm. Of note, ACP surrogates accurately reported on changes in patient preferences over one year, showing the positive impact of early conversation on longitudinal congruence.

Dr. Lyon hopes these results will encourage people to talk to their loved ones as soon as possible about ACP, not only during the current pandemic but into the future. “People can use what’s happening in the news as a trigger to begin these conversations,” she says. “The 1990 Patient Self-Determination Act (PSDA) encourages persons of all ages– including children and their parents– to decide the type and extent of medical care they want to accept or refuse if they become unable to make those decisions due to illness. Our research shows conversations matter.”

The original research paper, “Effect of FAmily CEntered (FACE®)Advance Care Planning on Longitudinal Congruence in End-of-Life Treatment Preferences: A Randomized Clinical Trial,” was recently published in AIDS and Behavior. Dr. Maureen E. Lyon, Ph.D., FABPP, of the Center for Translational Research/Children’s Research Institute, was the principal investigator of the trial and a co-senior of the paper.