Tag Archive for: infectious diseases

borrelia bacteria

First-of-its-kind study on impacts of Lyme disease in pregnancy and infant development

borrelia bacteria

Lyme disease is caused by the bacterium Borrelia burgdorferi.

Understanding the effects of Lyme disease on the developing fetal brain is essential to ensure timely prenatal and postnatal treatments to protect the fetus and newborn. In response to this need, Children’s National Hospital is leading a pilot study to establish the groundwork needed for a larger study to determine the effect of in utero exposure to Lyme disease on pregnancy and early childhood neurodevelopmental outcomes.

Why it’s important

“Insect-borne illnesses have more than doubled during the last twenty years as a result of multiple factors including environmental changes,” says Sarah Mulkey, M.D., Ph.D., principal investigator of the study and prenatal-neonatal neurologist at Children’s National Hospital. Dr. Mulkey is the Co-Director of the Congenital Infection Program at Children’s National Hospital and has led a long-term child outcome study of the mosquito-borne Zika virus infection in pregnancy and impacts on child neurodevelopment. She is now adding Lyme disease to her work on pregnancy and child outcomes. Lyme disease is transmitted to humans via an infected tick and can be acquired throughout much of the United States. “Very little is known about Lyme disease in pregnancy and if and how it may affect the fetus and impact child neurodevelopment,” said Dr. Mulkey.

This pilot study is funded by the Clinical Trials Network for Lyme and other Tickborne Diseases (CTN), supported by the Steven and Alexandra Cohen Foundation. Roberta DeBiasi, M.D., M.S., division chief of infectious diseases at Children’s National, is a CTN Node Principal Investigator. The study team at Children’s National works closely with members of the CTN as well as other Lyme disease-focused organizations and nonprofits to make sure that the pilot study addresses Lyme disease advocates’ research priorities in a scientifically rigorous way. “This is an important opportunity for us to engage with advocacy groups and others who have been stressing the need for this type of research for decades,” says Meagan Williams, M.S.P.H., C.C.R.C., the senior research coordinator for the study. “We know how important it is to maintain a patient-centered and trauma-sensitive lens in our work with families impacted by Lyme disease during pregnancy. We’ve been working hard to build this study in a way that centers our participants’ lived experiences and focuses on the topics they find important. We’re very grateful to have the support of Lyme disease focused organizations and advocates as we embark on this study because they know and have expressed exactly where the gaps are in the literature. It’s our job to do the work to fill those gaps.”

The big picture

This pilot study aims to build upon existing research, case studies and advocacy to assess developmental and other family impacts of Lyme disease exposure during pregnancy.

Especially as tick season begins in Washington, D.C., and surrounding regions, the investigators are determined to make sure that all eligible people diagnosed with Lyme disease during their pregnancy are aware of the study and have the opportunity to participate. Pregnant volunteers can sign up for participation in the study here. Volunteers may be eligible to join if they are currently pregnant, live in the U.S. or Canada and were diagnosed with Lyme disease during pregnancy or have post-treatment Lyme disease syndrome (PTLDS).

Anyone interested in sharing information about the study with their clients or colleagues may email mewilliams@childrensnational.org for access to the team’s recruitment toolkit that includes flyers, FAQs and other resources. “We have resources available for clinicians, public health professionals, friends and family members and anyone else who may be able to help us identify participants and spread the word about this important study,” Williams says.

The study is registered on ClinicalTrials.gov (NCT06026969). If you have questions about the study, please reach out to Meagan at mewilliams@childrensnational.org or email cnhlymestudy@gmail.com.

Members of the Columbia Zika virus research team

School entry neurodevelopmental outcomes of Zika-exposed Colombian children

Members of the Columbia Zika virus research team

The Children’s National Hospital Zika Research Team and collaborators from Biomelab, in Barranquilla, Colombia take a picture after a study visit in Sabanalarga, Colombia following the neurodevelopmental outcomes of children who had in utero exposure to Zika virus. Pictured from Children’s National Hospital: Dr. Sarah Mulkey, Regan Andringa-Seed, Margarita Arroyave-Wessel, and Dr. Madison Berl.

The long-term neurodevelopmental effects of antenatal Zika virus (ZIKV) exposure in children without congenital Zika syndrome (CZS) remain unclear, as few children have been followed to the age of starting primary school.

In a new study published in Pathogens, researchers found children with in utero ZIKV exposure appear to have an overall positive developmental trajectory at 4 to 5 years of age but may experience risks to neurodevelopment in areas of emotional regulation and adaptive mobility.

The hold up in the field

Children who were born during the ZIKV epidemic and who had in utero exposure to ZIKV are only now at the age to start school. Child neurodevelopmental outcome data has not been reported at the age of school entry for children with antenatal ZIKV exposure who do not have the severe birth defects of CZS.

“As these children approach the early school-age years, we aim to examine whether there are neurodevelopmental differences in executive function, motor ability, language development or scholastic skills as compared to a group of unexposed control participants from the same communities in Colombia,” says Sarah Mulkey, M.D., Ph.D., prenatal-neonatal neurologist in The Zickler Family Prenatal Pediatrics Institute at Children’s National Hospital and lead author of the study.

Moving the field forward

Building on previous findings, this study presents the longitudinal outcomes of a well-characterized Colombian cohort of ZIKV-exposed children without CZS at ages 4 to 5 years. These children have been seen for neurodevelopmental follow-up as infants and toddlers at approximately 6 months, 18 months and 3 years of age as part of an international collaboration between researchers in Barranquilla, Colombia and at Children’s National beginning in 2016. The objective of this study was to assess the multi-domain neurodevelopmental outcomes in 4 to 5-year-old children with antenatal ZIKV exposure without CZS compared to unexposed controls in Colombia.

Why we’re excited

Many of the children who had antenatal ZIKV exposure are making good progress in multiple areas of their neurodevelopment. However, the researchers found that children with antenatal ZIKV exposure have differences in areas of emotional regulation, executive function, mood and behavior which may relate to virus exposure during their early brain development.

“These areas of brain function are important for future academic achievement, employment, mental health and social relationships,” says Dr. Mulkey. “So, it will be important to continue to follow these children at older ages when they start school.”

Children’s National leads the way

Children’s National is a leader in conducting outcome studies of children born following antenatal ZIKV exposure. This study follows children in Colombia who are now 5 years old who were first studied while they were in the womb. These children have contributed unique longitudinal understanding to early child neurodevelopment following in utero exposure to ZIKV.

Dr. Mulkey is committed to studying the long-term neurodevelopmental impacts that viruses like Zika and SARS-CoV-2 have on infants born to mothers who were infected during pregnancy through research with the Congenital Infection Program at Children’s National and in collaboration with colleagues in Colombia.

Additional Children’s National authors include Meagan Williams M.S.P.H., C.C.R.C., senior research coordinator; Regan Andringa-Seed, clinical research coordinator, Margarita Arroyave-Wessel, clinical research coordinator; L. Gilbert Vezina, M.D., director, Neuroradiology Program; Dorothy Bulas, M.D., chief, Diagnostic Imaging and Radiology; Robert Podolsky, biostatistician.

Researchers showing paintings of zika virus

Dr. Sarah Mulkey and Children’s National clinical research coordinators in the Prenatal Pediatrics Institute and the Division of Pediatric Infectious Diseases display their paintings of the Zika virus. Pictured from left to right: Manuela Iglesias, Elizabeth Corn, Dr. Sarah Mulkey, Emily Ansusinha and Meagan Williams.

Roberta Debiasi

Roberta L. DeBiasi, M.D., M.S., named as Robert H. Parrott Professor of Pediatric Research

Roberta Debiasi

“This wonderful honor will greatly benefit the work of our Infectious Disease Division, and I look forward to working to utilize it to its full potential,” says Dr. DeBiasi.

Children’s National Hospital named Roberta L. DeBiasi, M.D., M.S., as the Robert H. Parrott Professor of Pediatric Research at Children’s National Hospital.

Dr. DeBiasi is chief of the Division of Pediatric Infectious Diseases at Children’s National. She leads the hospital’s response to emerging and highly contagious diseases and co-leads the Children’s National Congenital Infection Program. Dr. DeBiasi is a Principal Investigator in the Center for Translational Research at Children’s National Research Institute. She is a tenured Professor of Pediatrics and Microbiology, Immunology and Tropical Medicine at George Washington University.

About the award

Professorships at Children’s National support groundbreaking work on behalf of children and their families and foster new discoveries and innovations in pediatric medicine. These appointments carry prestige and honor that reflect the recipient’s achievements and donor’s forethought to advance and sustain knowledge. The Robert H. Parrott Professorship in Pediatric Research is one of 47 endowed chairs at Children’s National.

Dr. DeBiasi leads a multidisciplinary team of experts caring for children with infectious diseases and tracking disease transmission to help limit spread and prevent outbreaks. The Division of Pediatric Infectious Diseases is a key referral center in the Washington, D.C., area, helping thousands of patients each year. The division also promotes prevention through community outreach and education.

Dr. DeBiasi’s wide-ranging research portfolio includes studies and clinical trials focused on COVID-19, MIS-C, influenza, Ebola, Lyme disease, Zika and other infections affecting pregnant women, newborns and children. She is the institutional lead of the Lyme Clinical Trials Network, and Principal Investigator for a study focused on long term outcomes in children with all stages of Lyme Disease in partnership with the National Institutes of Health and National Institute of Allergy and Infectious Diseases. She also leads COVID-19 and MIS-C research at Children’s National and is Principal Investigator of a 3-year comprehensive longitudinal study of outcomes in children with COVID-19 and MIS-C in collaboration with the National Institutes of Health. Dr. DeBiasi has authored more than 120 original research, review articles and book chapters. Her research awards include the Infectious Diseases Society of America Young Investigator Award and the John Horsley Prize from the University of Virginia.

“This Chair is particularly meaningful to me because Dr. Parrott was a legendary leader,” says Dr. DeBiasi. “I have read and heard about his legacy at Children’s National for many years. Additionally, he was a virologist, and the focus of my academic career and research has been virology. This wonderful honor will greatly benefit the work of our Infectious Disease Division, and I look forward to working to utilize it to its full potential.”

About the donors

The Robert H. Parrott Professorship in Pediatric Research is supported by many generous donors, including the Charles Engelhard Foundation and the Diane and Norman Bernstein Foundation, Inc.  Through their vision and generosity, these donors are ensuring that Dr. DeBiasi and future holders of this professorship will launch bold, new initiatives to rapidly advance the field of pediatric infectious diseases, elevate our leadership and improve the health of children in the nation’s capital and around the world.

zika virus

Researcher to decipher how viruses affect the developing brain with nearly $1M NIH award

zika virus

Zika virus in blood with red blood cells, a virus which causes Zika fever found in Brazil and other tropical countries.

The National Institutes of Health (NIH) awarded Children’s National Hospital nearly $1M of research support toward uncovering the specific cellular response that happens inside a developing brain once it is infected with a virus, including how the neuron gets infected, and how it dies or survives. The research is expected to gather critical information that can inform prenatal neuro-precision therapies to prevent or attenuate the effects of endemic and pandemic viruses in the future.

“We need to use all of the information we have from ongoing and past pandemics to prevent tomorrow’s public health crisis,” said Youssef Kousa, MS, D.O., Ph.D., neonatal critical care neurologist and physician-scientist at Children’s National. “There is still here a whole lot to learn and discover. We could eventually — and this is the vision that’s inspiring us — prevent neurodevelopmental disorders before a baby is born by understanding more about the interaction between the virus, mother, fetus, and environment, among other factors.”

Different viruses, including HIV, CMV, Zika and rubella, injure the developing brain in very similar ways. This line of work was fostered first by the clinical research team led by Adre du Plessis, M.B.Ch.B., and Sarah Mulkey, M.D., supported by Catherine Limperopoulos, Ph.D., chief and director of the Developing Brain Institute at Children’s National.

The clinical research findings then led to the NIH support, which then inspired more basic science research. Fast forward to now, Kousa will study how Zika affects the human brain and extrapolate what is learned and discovered for a broader understanding of neurovirology.

The research program is supported by senior scientists and advisors, including Tarik Haydar, Ph.D., and Eric Vilain, M.D., Ph.D., both at Children’s National and Avindra Nath, M.D., at NIH, as well as other leading researchers at various U.S. centers.

“This is a team effort;” added Kousa, “I’m thankful to have a group of pioneering and seasoned researchers engaged with me throughout this process to provide invaluable guidance.”

Many viruses can harm the developing brain when they replicate in the absence of host defenses, including the gene regulatory networks responsible for the neuronal response. As a result, viral infections can lead to brain injury and neurodevelopmental delays and disorders such as intellectual disability, seizures that are difficult to treat, and vision or hearing loss.

The big picture

Youssef Kousa

Youssef Kousa, MS, D.O., Ph.D., neonatal critical care neurologist and physician-scientist at Children’s National.

The translational research supported by NIH with this award synergistically complements nationally recognized clinical research programs and ongoing prospective cohort studies at Children’s National to identify the full spectrum of neurodevelopmental clinical outcomes after prenatal Zika and other viral infections led by Dr. Mulkey and Roberta DeBiasi, M.D., M.S..

The award also builds upon strengths at the Children’s National Research & Innovation Campus, which is in proximity to federal science agencies. Children’s National experts from the Center for Genetic Medicine Research, known for pediatric genomic and precision medicine, joined forces with the Center of Neuroscience Research and the NIH-NINDS intramural research program to focus on examining prenatal and childhood neurological disorders.

Kousa received this competitive career development award from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number K08NS119882. The research content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The hold-up in the field

Many neurodevelopmental disorders are caused by endemic viruses, such as CMV, and by viral pandemics, including rubella as seen in the 1960s and Zika since 2015. By studying Zika and other prenatal viral infections, Kousa and team hope to gain deeper biological understanding of the viral effects toward developing therapies for anticipating, treating and preventing virally induced prenatal brain injury in the long-term future.

To date, little is known about how viruses affect developing neurons and, as a result, prenatal brain injury is not yet treatable. To bridge the gap towards prenatal neuro-precision therapies, the research explores how genes regulate neuronal developmental and viral clearance by innovatively integrating three systems:

  • Cerebral organoids, which illuminate how a neuron reacts to a viral infection
  • Pre-clinical models that link prenatal brain injury to postnatal neurodevelopmental outcomes
  • Populational genomics to identify human genetic risk or protective factors for prenatal brain injury

Given the scope and complexity of this issue, the international Zika Genetics Consortium, founded in 2015 by Kousa and a team of leading investigators across the world, provides critical samples and resources for the third arm of the research by performing comprehensive genomic analyses using sequencing data collected from diverse human populations throughout Central and South America, which are not as heavily sequenced as Western populations. Through partnerships with the Centers for Disease Control and Prevention and NIH, the consortium’s database and biorepository houses thousands of patient records and biospecimens for research studies to better understand how viruses affect the developing human brain.

“It is inspiring to imagine that, in the longer term, we could recognize early on the level of brain-injury risk faced by a developing fetus and have the tools to mitigate ensuing complications,” said Kousa. “What is driving this research is the vision that one day, brain injury could be prevented from happening before a baby is born.”

pregnant hispanic woman

COVID-19’s impact on pregnant women and their babies

pregnant hispanic woman

While pregnant women are at higher risk of severe illness, coronavirus can also trigger inflammatory and vascular responses in the placenta during critical periods of fetal development in symptomatic and asymptomatic cases.

Pregnant women should get vaccinated to minimize the detrimental health effects COVID-19 has on the placenta, the fetus and the newborn, states Roberta L. DeBiasi, M.D., M.S., division chief of Pediatric Infectious Diseases at Children’s National Hospital in an editorial published in The Journal of Infectious Diseases.

The editorial provides a comprehensive review of what is known about the harmful effects of SARS-CoV-2 infection in pregnant women themselves, the effects on their newborns, the negative impact on the placenta and what still is unknown amid the rapidly evolving field. The safety and efficacy of vaccination of pregnant women are also addressed.

While pregnant women are at higher risk of severe illness, the virus can also trigger inflammatory and vascular responses in the placenta during critical periods of fetal development in symptomatic and asymptomatic cases.

In this piece, Dr. DeBiasi comments on two related studies published in the same issue, Guan et al. and Shook et al., demonstrating pathologic findings in women’s placentas who had COVID-19 during pregnancy. Guan et al. published a detailed analysis of a stillbirth resulting from the delta variant infection during the third trimester.

“The authors present a highly plausible mechanism of stillbirth, namely that the virus-induced proinflammatory state ultimately led to placental abruption,” said Dr. DeBiasi.

Shook et al. presented a case series of pregnant women infected with the delta variant associated with stillbirth in two cases and one with severe neonatal illness.

“Taking the studies together, it’s evident that if a pregnant woman gets COVID-19 they’re at an increased risk of severe infection,” says DeBiasi. “They’re also at increased risk of adverse pregnancy outcomes, due to effects on the placenta, which may vary with specific circulating variants.”

Previous studies have documented that the placenta may be detrimentally affected by SARS-CoV-2 infection of the mother. However, maternal comorbidities such as hypertension, preeclampsia and gestational diabetes could also contribute to these findings.

“Despite these previous studies, the precise mechanisms of placental injury are still not clear and require further evaluation,” says Dr. DeBiasi. “Future research should include appropriate controls to better discern nonspecific versus SARS-CoV-2 specific effects and mechanisms of injury.”

Even though these potential risks exist, the vaccination rate among pregnant women is low. Dr. DeBiasi writes that recent publications have demonstrated vaccine efficacy and safety during pregnancy through programs that tracked the use in pregnant women. This data supports that COVID-19 vaccine offers another layer of protection to pregnant women since infants are not yet eligible for vaccination despite the fact that the youngest infants and children are among the most at risk among children for hospitalization.

boy in hospital bed

Long-term, controlled studies needed to chart optimal MIS-C immunotherapy

boy in hospital bed

Roberta L. DeBiasi, M.D., chief of the Division of Pediatric Infectious Diseases at Children’s National Hospital, cautions that two new studies in the New England Journal of Medicine present seemingly conflicting findings about which treatments for MIS-C are optimal.

Multisystem inflammatory disease in children (MIS-C) has affected nearly 4,000 children in the United States in the last year. Two major studies appearing in the June edition of the New England Journal of Medicine seek to better define which immunotherapy treatments or combinations of treatments — intravenous immune globulin (IVIG), glucocorticoids or biologics — do the best job of combating the syndrome’s effects.

But Roberta L. DeBiasi, M.D., chief of the Division of Pediatric Infectious Diseases at Children’s National Hospital, cautions that though these two studies present seemingly conflicting findings about which treatments are optimal, neither study can provide a complete picture of efficacy, in part due to their retrospective and observational study design and population made up of patients from many different centers. True consensus will likely be found, she writes in an editorial that accompanies the studies in the journal, through single-center prospective cohort studies with standardized treatment approaches and long-term follow-up on outcomes.

“While there is a diagnostic criterion and an agreed upon need to induce a rapid therapy for MIS-C, the scientific community has not been able to agree on specific and optimal forms of immunomodulatory therapy,” she writes.

Despite efforts by the study authors to use statistical methods and modeling to control for variations in treatment applications from center to center, the study data is limited by the fact that the therapies have already been administered, in various combinations, based on conditions at each center where a  child was treated and not on a common set of treatment criteria.

Another challenge for generalizing from the findings of these studies is a mismatch in time. The data collected from the two published studies have two different time frames: before and after variants emerged or at various points during different waves of COVID-19 circulation in the U.S.

“Depending on the strain of initial infection and/or subsequent exposure, the dysregulated hyperimmune response of MIS-C could change,” Dr. DeBiasi says. And along with it, how patients respond to a particular treatment or combination of treatments.

Also, she notes it is too soon for any consortia to assess the impact of these therapies on longer-term outcomes, “specifically, comparative efficacy for progression or resolution of coronary abnormalities and prolonged or permanent cardiac dysfunction or scarring.”

Dr. DeBiasi concludes her editorial with a call for well-characterized large prospective cohort studies at single centers, and systematic and long-term follow-up for cardiac and non-cardiac outcomes in children with MIS-C. Data from these studies will be a crucial determinant of the best set of treatment guidelines for immunotherapies to treat MIS-C. Without findings from these types of studies, the selection of the most efficacious treatments is still unknown.

Read the full editorial in the New England Journal of Medicine: Immunotherapy for MIS-C: IVIG, Glucocorticoids, and Biologics

HIV Viruses

New pre-clinical model could hold the key to better HIV treatments

HIV Viruses

A team led by researchers at Weill Cornell Medicine and Children’s National Hospital has developed a unique pre-clinical model that enables the study of long-term HIV infection, and the testing of new therapies aimed at curing the disease.

A team led by researchers at Weill Cornell Medicine and Children’s National Hospital has developed a unique pre-clinical model that enables the study of long-term HIV infection, and the testing of new therapies aimed at curing the disease.

Ordinary subjects in this model cannot be infected with HIV, so previous HIV pre-clinical models have used subjects that carry human stem cells or CD4 T cells, a type of immune cell that can be infected with HIV. But these models tend to have limited utility because the human cells soon perceive the tissues of their hosts as “foreign,” and attack—making the subject gravely ill.

By contrast, the new pre-clinical model, described in a paper in the Journal of Experimental Medicine on 14 May, avoids this problem by using a subset of human CD4 cells that mostly excludes the cells that would attack the subject’s tissue. The researchers showed that the subject can usefully model the dynamics of long-term HIV infection, including the virus’s response to experimental therapies.

“We expect this to be a valuable and widely used tool for studying the basic science of HIV infection, and for speeding the development of better therapies,” said co-first author Dr. Chase McCann. During the study, Dr. McCann was a Weill Cornell Graduate School student in the laboratory of senior author Dr. Brad Jones, associate professor of immunology in medicine in the Division of Infectious Diseases at Weill Cornell Medicine. Dr. McCann, who was supported at Weill Cornell by a Clinical and Translational Science Center (CTSC) TL1 training award, is now the Cell Therapy Lab Lead in the Center for Cancer and Immunology Research at Children’s National Hospital in Washington, D.C. The other co-first authors of the study are Dr. Christiaan van Dorp of Los Alamos National Laboratory and Dr. Ali Danesh, a senior research associate in medicine at Weill Cornell Medicine.

The invention of the new pre-clinical model is part of a wider effort to develop and test cell therapies against HIV infection. Cell therapies, such as those using the patient’s own engineered T cells, are increasingly common in cancer treatment and have achieved some remarkable results. Many researchers hope that a similar strategy can work against HIV and can potentially be curative. But the lack of good pre-clinical models has hampered the development of such therapies.

Drs. Jones and McCann and their colleagues showed in the study that the cell-attacks-host problem found in prior pre-clinical models is chiefly due to so-called “naïve” CD4 cells. These are CD4 cells that have not yet been exposed to targets, and apparently include a population of cells that can attack various proteins. When the researchers excluded naïve CD4 cells and instead used only “memory” CD4 cells, which circulate in the blood as sentinels against infection following exposure to a specific pathogen, the cells survived indefinitely in the subject without causing major damage to their hosts.

The researchers observed that the human CD4 cells also could be infected and killed by HIV, or protected by standard anti-HIV drugs, essentially in the same way that they are in humans. Thus, they showed that the subject, which they termed “participant-derived xenograft” or PDX, served as a workable model for long-term HIV infection. This term is akin to the “patient-derived xenograft” PDX models used to study cancer therapies, while recognizing the contributions of people with HIV as active participants in research.

Lastly, the researchers used the new model to study a prospective new T-cell based therapy, very similar to one that is now being tested against cancers. They put memory CD4 T cells from a human donor into the subject to permit HIV infection, and then, after infection was established, treated the subject with another infusion of human T cells, these being CD8-type T cells, also called “killer T cells.”

The killer T cells were from the same human donor and could recognize a vulnerable structure on HIV — so that they attacked the virus wherever they found it within the subject. To boost the killer T cells’ effectiveness, the researchers supercharged them with a T cell-stimulating protein called IL-15.

The treatment powerfully suppressed HIV in the subject. And although, as often seen in human cases, the virus ultimately evolved to escape recognition by the killer T cells, the ease of use of the pre-clinical model allowed the researchers to monitor and study these long-term infection and viral escape dynamics in detail.

“I think that the major impact of this model will be its acceleration of the development of T cell-based therapies that can overcome this problem of viral escape,” Dr. Jones said.

He and his laboratory are continuing to study such therapies using the new pre-clinical model, with engineered T cells from Dr. McCann’s laboratory and others.

A version of this story appeared on the Weill Cornell Medicine newsroom.