infection Archives

Once overlooked cellular messengers could combat antibiotic resistance

March 18, 2020

Children’s National Hospital researchers for the first time have isolated bacterial extracellular vesicles from the blood of healthy donors. The team theorizes that the solar eclipse lookalikes contain important signaling proteins and chromatin, DNA from the human host.

Children’s National Hospital researchers for the first time have isolated bacterial extracellular vesicles from the blood of healthy donors, a critical step to better understanding the way gut bacteria communicate with the rest of the body via the bloodstream.

For decades, researchers considered circulating bacterial extracellular vesicles as bothersome flotsam to be jettisoned as they sought to tease out how bacteria that reside in the gut whisper messages to the brain.

There is a growing appreciation that extracellular vesicles – particles that cells naturally release – actually facilitate intracellular communication.

“In the past, we thought they were garbage or noise,” says Robert J. Freishtat, M.D., MPH, associate director, Center for Genetic Medicine Research at Children’s National Research Institute. “It turns out what we throw away is not trash.”

Kylie Krohmaly, a graduate student in Dr. Freishtat’s laboratory, has isolated from blood, extracellular vesicles from Escherichia coli and Haemophilus influenzae, common bacteria that colonize the gut, and validated the results via electron microscopy.

“The images are interesting because they look like they have a bit of a halo around them or penumbra,” Krohmaly says.

The team theorizes that the solar eclipse lookalikes contain important signaling proteins and chromatin, DNA from the human host.

“It’s the first time anyone has pulled them out of blood. Detecting them is one thing. Pulling them out is a critical step to understanding the language the microbiome uses as it speaks with its human host,” Dr. Freishtat adds.

Krohmaly’s technique is so promising that the Children’s National team filed a provisional patent.

The Children’s research team has devised a way to gum up the cellular works so that bacteria no longer become antibiotic resistant. Targeted bacteria retain the ability to make antibiotic-resistance RNA, but like a relay runner dropping rather than passing a baton, the bacteria are thwarted from advancing beyond that step. And, because that gene is turned off, the bacteria are newly sensitive to antibiotics – instead of resistant bacteria multiplying like clockwork these bacteria get killed.

“Our plan is to hijack this process in order to turn off antibiotic-resistance genes in bacteria,” Dr. Freishtat says. “Ultimately, if a child who has an ear infection can no longer take amoxicillin, the antibiotic would be given in tandem with the bacteria-derived booster to turn off bacteria’s ability to become antibiotic resistant. This one-two punch could become a novel way of addressing the antibiotic resistance process.”

ISEV2020 Annual Meeting presentation
(Timing may be subject to change due to COVID-19 safety precautions)
Oral with poster session 3: Neurological & ID
Saturday May 23, 2020, 5 p.m. to 5:05 p.m. (ET)
“Detection of bacterial extracellular vesicles in blood from healthy volunteers”
Kylie Krohmaly, lead author; Claire Hoptay, co-author; Andrea Hahn, M.D., MS, infectious disease specialist and co-author; Robert J. Freishtat, M.D., MPH, associate director, Center for Genetic Medicine Research at Children’s National Research Institute and senior author.

A bronchopulmonary dysplasia primer to guide clinicians and researchers

February 14, 2020

newborn in incubator

Six months in the writing, the “Bronchopulmonary Dysplasia Primer” published recently by Nature Reviews will be the gold standard review on this topic for years to come.

The term bronchopulmonary dysplasia, or BPD, was first coined in 1967 to describe a chronic lung disease of preterm newborns after treatment with supplemental oxygen via mechanical ventilation in an effort to save their lives. Back then, infants had 50-50 odds of surviving.

In the intervening years, survival has improved and the characteristics of BPD have evolved. Now, BPD is the most common complication of preterm birth for infants born at fewer than 28 weeks’ gestation, as more and more newborns survive premature birth. Hence, the primer.

“The contributing authors are some of the biggest thinkers on this topic,” says Robin H. Steinhorn, M.D., senior vice president, Center for Hospital-Based Specialties, at Children’s National Hospital and author of the section about BPD diagnosis, screening and prevention. “This document will guide clinical education and investigators in the field of BPD. I anticipate this will be the definitive review article on the subject for the next several years.”

Gestational age and low birth weight remain the most potent predictors of BPD. Some 50,000 extremely low gestational age newborns are born each year in the U.S. About 35% will develop some degree of BPD, according to the primer authors.

These newborns are introduced to life outside the womb well before their lungs are ready. Indeed, the pulmonary surfactants needed for normal lung function – a complex mixture of phospholipids that reduce surface tension within the lungs – don’t differentiate until late in pregnancy. Infants who persistently need respiratory support after the 14^th day of life are at the highest risk of being diagnosed with BPD at 36 weeks, the coauthors note.

A number of complicating factors can come into play, including maternal diet; fetal exposure to maternal smoking and infection; structural issues such as pre-eclampsia; acute injury from mechanical ventilation and supplemental oxygen; as well as the body’s halting efforts to repair injured, inflamed lung tissue.

“The good news is the number of the smallest and youngest preterm infants who survive extreme preterm birth has steadily increased. Neonatal intensive care units, like our award-winning NICU, now routinely care for babies born at 22 weeks’ gestation,” Dr. Steinhorn says.

Treatment strategies include:

Reducing exposure to intubation and ventilation.
Leveraging respiratory stimulants, like caffeine.
Postnatal steroid therapy.

“Children’s National Hospital is the only center in our immediate region that provides comprehensive care for infants and children with severe BPD,” Dr. Steinhorn adds. “As the population of vulnerable and fragile infants has grown, we have invested in the equipment and the personnel – including at the Hospital for Sick Children Pediatric Center (HSC) – to create a very safe and supportive environment that improves survival and quality of life.”

Some preterm infants spend their first 9 to 10 months of life at Children’s National, and their days are filled with concentrated physical, occupational and speech therapy, as well as music and play therapy to hasten their rehabilitation.

Once their medical condition stabilizes, they transition to HSC to focus more intently on rehabilitation.

“We see HSC as filling a very important role in their care. When our children graduate to HSC, they are going for ongoing care of their lung disease, but also their ongoing rehabilitation. At HSC, they focus on creating the most normal life that we can possibly create and, over time, that is a life free of ventilators and tracheostomy tubes.”

In addition to Dr. Steinhorn, BPD Primer co-authors include Bernard Thébaud, Children’s Hospital of Eastern Ontario; Kara N. Goss, University of Wisconsin-Madison; Matthew Laughon, The University of North Carolina at Chapel Hill; Jeffrey A. Whitsett and Alan H. Jobe, Cincinnati Children’s Hospital Medical Center; Steven H. Abman, Children’s Hospital Colorado; Judy L. Aschner, Joseph M. Sanzari Children’s Hospital; Peter G. Davis, The Royal Women’s Hospital; Sharon A. McGrath- Morrow, Johns Hopkins University School of Medicine; and Roger F. Soll, University of Vermont.

Financial support for the research described in this post was provided by the National Institutes of Health under grant Nos. U01HL122642, U01HL134745, RO1HL68702, R01HL145679, U01HL12118-01 and K24 HL143283; the Australian National Health and Medical Research Council; the Canadian Institute for Health Research; Stem Cell Network and the Ontario Institute for Regenerative Medicine.

Extreme difficulty breathing and swallowing linked to teen’s vaping?

February 5, 2020

After a teen was transferred to Children’s National Hospital suffering from severe difficulty breathing and swallowing, a multidisciplinary team continued the detective work and surmises that vaping was to blame for her unusual symptoms.

A teenage girl with no hint of prior asthma or respiratory illness began to feel hoarseness in her throat and a feeling that she needed to clear her throat frequently. Within a few weeks, her hoarseness and throat-clearing worsened with early morning voice loss and feeling as if food were lodged in her throat. She started having trouble swallowing and began to avoid food all together.

Her pediatrician prescribed loratadine for suspected allergies to no avail. Days later, an urgent care center prescribed a three-day course of prednisone. For a few days, she felt a little better, but went back to feeling like she was breathing “through a straw.” After going to an emergency room with acute respiratory distress and severe difficulty swallowing, staff tried intravenous dexamethasone, ampicillin/sulbactam, and inhaled racemic epinephrine and arranged for transfer.

When she arrived at Children’s National Hospital, a multidisciplinary team continued the detective work with additional testing, imaging and bloodwork.

Examining her throat confirmed moderate swelling and a partially obstructed airway draped with thick chartreuse-colored mucus. The teen had no history of an autoimmune disorder, no international travel and no exposure to animals. She had no fever and had received all her scheduled immunizations.

“With epiglottitis – an inflammation of the flap found at the base of the tongue that prevents food from entering the trachea – our first concern is that an underlying infection is to blame,” says Michael Jason Bozzella, D.O., MS, a third-year infectious diseases fellow and lead author of the case report published Feb. 5, 2020, in Pediatrics. “We tested her specimens in a number of ways for a host of respiratory pathogens, including human rhino/enterovirus, respiratory syncytial virus, influenza, Epstein-Barr virus, Streptococcus and more. All negative. We also looked for more atypical infections with bacteria, like Arcanobacterium, Mycoplasma and Gonorrhea. Those were all negative as well,” Dr. Bozzella adds.

She slowly improved during a seven-day initial hospital stay, though soon returned for another six-day hospital stay after it again became excruciatingly painful for her to swallow.

Every throat culture and biopsy result showed no evidence of fungal, bacterial or viral infection, acid-fast bacilli or other malignancy. But in speaking with doctors, the teen had admitted to using candy-and fruit-flavored e-cigarettes three to five times with her friends over the two months preceding her symptoms. The last time she vaped was two weeks before her unusual symptoms began.

According to the Centers for Disease Control and Prevention, 2,668 people in the U.S. have been hospitalized for e-cigarette or vaping product use-associated lung injury, as of Jan. 14, 2020. The Children’s National case report’s authors say the increasing use of vaping products by teenagers highlights the potential for unknown health risks to continue to grow.

“This teenager’s use of e-cigarettes is the most plausible reason for this subacute epiglottitis diagnosis, a condition that can become life-threatening,” says Kathleen Ferrer, M.D., a hospitalist at Children’s National and the case report’s senior author. “This unusual case adds to a growing list of toxic effects attributable to vaping. While we normally investigate infectious triggers, like Streptococci, Staphylococci and Haemophilus, we and other health care providers should also consider e-cigarettes as we evaluate oro-respiratory complaints.”

In addition to Drs. Bozzella and Ferrer, Children’s National case report co-authors include Matthew Allen Magyar, M.D., a hospitalist; and Roberta L. DeBiasi, M.D., MS, chief of the Division of Pediatric Infectious Diseases.

Critters bugging! Test your infectious disease knowledge

September 10, 2019

Searching for the molecular underpinnings of asthma exacerbations

August 30, 2019

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Fewer than 60% of young women diagnosed with STIs in emergency departments fill scripts

May 29, 2019

Fewer than 60% of young women diagnosed with sexually transmitted infections (STIs) in the emergency department fill prescriptions for antimicrobial therapy to treat these conditions, according to a research letter published online May 28, 2019, by JAMA Pediatrics.

Adolescents make up nearly half of the people diagnosed with sexually transmitted infections each year. According to the Centers for Disease Control and Prevention, untreated sexually transmitted diseases in women can cause pelvic inflammatory disease (PID), an infection of the reproductive organs that can complicate getting pregnant in the future.

“We were astonished to find that teenagers’ rates of filling STI prescriptions were so low,” says Monika K. Goyal, M.D., MSCE, assistant chief of Children’s Division of Emergency Medicine and Trauma Services and the study’s senior author. “Our findings demonstrate the imperative need to identify innovative methods to improve treatment adherence for this high-risk population.”

The retrospective cohort study, conducted at two emergency departments affiliated with a large, urban, tertiary care children’s hospital, enrolled adolescents aged 13 to 19 who were prescribed antimicrobial treatment from Jan. 1, 2016, to Dec. 31, 2017, after being diagnosed with PID or testing positive for chlamydia.

Of 696 emergency department visits for diagnosed STIs, 208 teenagers received outpatient prescriptions for antimicrobial treatments. Only 54.1% of those prescriptions were filled.

“Teenagers may face a number of hurdles when it comes to STI treatment, including out-of-pocket cost, access to transportation and confidentiality concerns,” Dr. Goyal adds.

Future studies will attempt to identify barriers to filling prescriptions in order to inform development of targeted interventions based in the emergency department that promote adherence to STI treatment.

In addition to Dr. Goyal, study co-authors include Lead Author, Alexandra Lieberman, BA, The George Washington University School of Medicine & Health Sciences; and co-authors Gia M. Badolato, MPH, and Jennifer Tran, PA-C, MPH, both of Children’s National.

dnDSA and African American ethnicity linked with thickening of blood vessels after kidney transplant

May 8, 2019

Emerging evidence links dnDSA with increased risk of accelerated systemic hardening of the arteries (arteriosclerosis) and major cardiac events in adult organ transplant recipients. However, this phenomenon has not been studied extensively in children who receive kidney transplants.

Children who developed anti-human leukocyte antibodies against their donor kidney, known as de novo donor-specific antibodies (dnDSA), after kidney transplant were more likely to experience carotid intima-media thickening (CIMT) than those without these antibodies, according to preliminary research presented May 7, 2019, during the 10th Congress of the International Pediatric Transplant Association.

dnDSA play a key role in the survival of a transplanted organ. While human leukocyte antibodies protect the body from infection, dnDSA are a major cause of allograft loss. CIMT measures the thickness of the intima and media layers of the carotid artery and can serve as an early marker of cardiac disease.

Emerging evidence links dnDSA with increased risk of accelerated systemic hardening of the arteries (arteriosclerosis) and major cardiac events in adult organ transplant recipients. However, this phenomenon has not been studied extensively in children who receive kidney transplants.

To investigate the issue, Children’s researchers enrolled 38 children who had received kidney transplants and matched them by race with 20 healthy children. They measured their CIMT, blood pressure and lipids 18 months and 30 months after their kidney transplants. They monitored dnDSA at 18 months and 30 months after kidney transplant. The transplant recipients’ median age was 11.3 years, 50 percent were African American, and 21% developed dnDSA.

“In this prospective controlled cohort study, we compared outcomes among patients who developed dnDSA with transplant recipients who did not develop dnDSA and with race-matched healthy kids,” says Kristen Sgambat, Ph.D., a pediatric renal dietitian at Children’s National who was the study’s lead author. “Children with dnDSA after transplant had 5.5% thicker CIMT than those who did not have dnDSA. Being African American was also independently associated with a 9.2% increase in CIMT among transplant recipients.”

Additional studies will need to be conducted in larger numbers of pediatric kidney transplant recipients to verify this preliminary association, Sgambat adds.

10th Congress of the International Pediatric Transplant Association presentation:

“Circulating de novo donor-specific antibodies and carotid intima-media thickness in pediatric kidney transplant recipients.”

Kristen Sgambat, Ph.D., pediatric renal dietitian and study lead author; Sarah Clauss, M.D., cardiologist and study co-author; and Asha Moudgil, M.D., Medical Director, Transplant and senior study author, all of Children’s National.

Looking for ‘help’ signals in the blood of newborns with HIE

April 29, 2019

“This data support our hypothesis that a panel of biomarkers – not a one-time test for a single biomarker – is needed to adequately determine the risk and timing of brain injury for babies with HIE,” says An N. Massaro, M.D.

Measuring a number of biomarkers over time that are produced as the body responds to inflammation and injury may help to pinpoint newborns who are more vulnerable to suffering lasting brain injury due to disrupted oxygen delivery and blood flow, according to research presented during the Pediatric Academic Societies 2019 Annual Meeting.

Hypoxic-ischemic encephalopathy (HIE) happens when blood and oxygen flow are disrupted around the time of birth and is a serious birth complication for full-term infants. To lessen the chance of these newborns suffering permanent brain injury, affected infants undergo therapeutic cooling, which temporarily lowers their body temperatures.

“Several candidate blood biomarkers have been investigated in HIE but we still don’t have one in clinical use. We need to understand how these markers change over time before we can use them to direct care in patients,” says An N. Massaro, M.D., co-director of the Neonatal Neurocritical Care Program at Children’s National and the study’s senior author. “The newborns’ bodies sent out different ‘help’ signals that we detected in their bloodstream, and the markers had strikingly different time courses. A panel of plasma biomarkers has the potential to help us identify infants most in need of additional interventions, and to help us understand the most optimal timing for those interventions.”

Past research has keyed in on inflammatory cytokines and Tau protein as potential biomarkers of brain injury for infants with HIE who are undergoing therapeutic cooling. The research team led by Children’s faculty wanted to gauge which time periods to measure such biomarkers circulating in newborns’ bloodstreams. They enrolled 85 infants with moderate or severe HIE and tapped unused blood specimens that had been collected as cooling began, as well as 12, 24, 72 and 96 hours later. The infants’ mean gestational age was 38.7 weeks, their mean birth weight was about 7 pounds (3.2 kilograms), and 19% had severe brain disease (encephalopathy).

Cytokines – chemicals like Interleukin (IL) 6, 8 and 10 that regulate how the body responds to infection, inflammation and trauma – peaked in the first 24 hours of cooling for most of the newborns. However, the highest measure of Tau protein for the majority of newborns was during or after the baby’s temperature was restored to normal.

“After adjusting for clinical severity of encephalopathy and five-minute Apgar scores, IL-6, IL-8 and IL-10 predicted adverse outcomes, like severe brain injury or death, as therapeutic hypothermia began. By contrast, Tau protein measurements predicted adverse outcomes during and after the infants were rewarmed,” Dr. Massaro says.

IL-6 and IL-8 proteins are pro-inflammatory cytokines while IL-10 is considered anti-inflammatory. These chemicals are released as a part of the immune response to brain injury. Tau proteins are abundant in nerve cells and stabilize microtubules.

“This data support our hypothesis that a panel of biomarkers – not a one-time test for a single biomarker – is needed to adequately determine the risk and timing of brain injury for babies with HIE,” she adds.

Pediatric Academic Societies 2019 Annual Meeting presentation

“Serial plasma biomarkers of brain injury in infants with hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH).”
- Saturday, April 27, 2019, 6 p.m. (EST)

Meaghan McGowan, lead author; Alexandra C. O’Kane, co-author; Gilbert Vezina, M.D., director, Neuroradiology Program and co-author; Tae Chang, M.D., director, Neonatal Neurology Program and co-author; and An N. Massaro, M.D., co-director of the Neonatal Neurocritical Care Program and senior author; all of Children’s National; and co-author Allen Everett, of Johns Hopkins School of Medicine.

Research and Education Week honors innovative science

April 19, 2019

Billie Lou Short, M.D., received the Ninth Annual Mentorship Award in Clinical Science.

People joke that Billie Lou Short, M.D., chief of Children’s Division of Neonatology, invented extracorporeal membrane oxygenation, known as ECMO for short. While Dr. Short did not invent ECMO, under her leadership Children’s National was the first pediatric hospital to use it. And over decades Children’s staff have perfected its use to save the lives of tiny, vulnerable newborns by temporarily taking over for their struggling hearts and lungs. For two consecutive years, Children’s neonatal intensive care unit has been named the nation’s No. 1 for newborns by U.S. News & World Report. “Despite all of these accomplishments, Dr. Short’s best legacy is what she has done as a mentor to countless trainees, nurses and faculty she’s touched during their careers. She touches every type of clinical staff member who has come through our neonatal intensive care unit,” says An Massaro, M.D., director of residency research.

For these achievements, Dr. Short received the Ninth Annual Mentorship Award in Clinical Science.

Anna Penn, M.D., Ph.D., has provided new insights into the central role that the placental hormone allopregnanolone plays in orderly fetal brain development, and her research team has created novel experimental models that mimic some of the brain injuries often seen in very preterm babies – an essential step that informs future neuroprotective strategies. Dr. Penn, a clinical neonatologist and developmental neuroscientist, “has been a primary adviser for 40 mentees throughout their careers and embodies Children’s core values of Compassion, Commitment and Connection,” says Claire-Marie Vacher, Ph.D.

For these achievements, Dr. Penn was selected to receive the Ninth Annual Mentorship Award in Basic and Translational Science.

The mentorship awards for Drs. Short and Penn were among dozens of honors given in conjunction with “Frontiers in Innovation,” the Ninth Annual Research and Education Week (REW) at Children’s National. In addition to seven keynote lectures, more than 350 posters were submitted from researchers – from high-school students to full-time faculty – about basic and translational science, clinical research, community-based research, education, training and quality improvement; five poster presenters were showcased via Facebook Live events hosted by Children’s Hospital Foundation.

Two faculty members won twice: Vicki Freedenberg, Ph.D., APRN, for research about mindfulness-based stress reduction and Adeline (Wei Li) Koay, MBBS, MSc, for research related to HIV. So many women at every stage of their research careers took to the stage to accept honors that Naomi L.C. Luban, M.D., Vice Chair of Academic Affairs, quipped that “this day is power to women.”

Here are the 2019 REW award winners:

2019 Elda Y. Arce Teaching Scholars Award
Barbara Jantausch, M.D.
Lowell Frank, M.D.

Suzanne Feetham, Ph.D., FAA, Nursing Research Support Award
Vicki Freedenberg, Ph.D., APRN, for “Psychosocial and biological effects of mindfulness-based stress reduction intervention in adolescents with CHD/CIEDs: a randomized control trial”
Renee’ Roberts Turner for “Peak and nadir experiences of mid-level nurse leaders”

2019-2020 Global Health Initiative Exploration in Global Health Awards
Nathalie Quion, M.D., for “Latino youth and families need assessment,” conducted in Washington
Sonia Voleti for “Handheld ultrasound machine task shifting,” conducted in Micronesia
Tania Ahluwalia, M.D., for “Simulation curriculum for emergency medicine,” conducted in India
Yvonne Yui for “Designated resuscitation teams in NICUs,” conducted in Ghana
Xiaoyan Song, Ph.D., MBBS, MSc, “Prevention of hospital-onset infections in PICUs,” conducted in China

Ninth Annual Research and Education Week Poster Session Awards

Basic and Translational Science
Faculty: Adeline (Wei Li) Koay, MBBS, MSc, for “Differences in the gut microbiome of HIV-infected versus HIV-exposed, uninfected infants”
Faculty: Hayk Barseghyan, Ph.D., for “Composite de novo Armenian human genome assembly and haplotyping via optical mapping and ultra-long read sequencing”
Staff: Damon K. McCullough, BS, for “Brain slicer: 3D-printed tissue processing tool for pediatric neuroscience research”
Staff: Antonio R. Porras, Ph.D., for “Integrated deep-learning method for genetic syndrome screening using facial photographs”
Post docs/fellows/residents: Lung Lau, M.D., for “A novel, sprayable and bio-absorbable sealant for wound dressings”
Post docs/fellows/residents: Kelsey F. Sugrue, Ph.D., for “HECTD1 is required for growth of the myocardium secondary to placental insufficiency”
Graduate students: Erin R. Bonner, BA, for “Comprehensive mutation profiling of pediatric diffuse midline gliomas using liquid biopsy”
High school/undergraduate students: Ali Sarhan for “Parental somato-gonadal mosaic genetic variants are a source of recurrent risk for de novo disorders and parental health concerns: a systematic review of the literature and meta-analysis”

Clinical Research
Faculty: Amy Hont, M.D., for “Ex vivo expanded multi-tumor antigen specific T-cells for the treatment of solid tumors”
Faculty: Lauren McLaughlin, M.D., for “EBV/LMP-specific T-cells maintain remissions of T- and B-cell EBV lymphomas after allogeneic bone marrow transplantation”

Staff: Iman A. Abdikarim, BA, for “Timing of allergenic food introduction among African American and Caucasian children with food allergy in the FORWARD study”
Staff: Gelina M. Sani, BS, for “Quantifying hematopoietic stem cells towards in utero gene therapy for treatment of sickle cell disease in fetal cord blood”
Post docs/fellows/residents: Amy H. Jones, M.D., for “To trach or not trach: exploration of parental conflict, regret and impacts on quality of life in tracheostomy decision-making”
Graduate students: Alyssa Dewyer, BS, for “Telemedicine support of cardiac care in Northern Uganda: leveraging hand-held echocardiography and task-shifting”
Graduate students: Natalie Pudalov, BA, “Cortical thickness asymmetries in MRI-abnormal pediatric epilepsy patients: a potential metric for surgery outcome”
High school/undergraduate students: Kia Yoshinaga for “Time to rhythm detection during pediatric cardiac arrest in a pediatric emergency department”

Community-Based Research
Faculty: Adeline (Wei Li) Koay, MBBS, MSc, for “Recent trends in the prevention of mother-to-child transmission (PMTCT) of HIV in the Washington, D.C., metropolitan area”
Staff: Gia M. Badolato, MPH, for “STI screening in an urban ED based on chief complaint”
Post docs/fellows/residents: Christina P. Ho, M.D., for “Pediatric urinary tract infection resistance patterns in the Washington, D.C., metropolitan area”
Graduate students: Noushine Sadeghi, BS, “Racial/ethnic disparities in receipt of sexual health services among adolescent females”

Education, Training and Program Development
Faculty: Cara Lichtenstein, M.D., MPH, for “Using a community bus trip to increase knowledge of health disparities”
Staff: Iana Y. Clarence, MPH, for “TEACHing residents to address child poverty: an innovative multimodal curriculum”
Post docs/fellows/residents: Johanna Kaufman, M.D., for “Inpatient consultation in pediatrics: a learning tool to improve communication”
High school/undergraduate students: Brett E. Pearson for “Analysis of unanticipated problems in CNMC human subjects research studies and implications for process improvement”

Quality and Performance Improvement
Faculty: Vicki Freedenberg, Ph.D., APRN, for “Implementing a mindfulness-based stress reduction curriculum in a congenital heart disease program”
Staff: Caleb Griffith, MPH, for “Assessing the sustainability of point-of-care HIV screening of adolescents in pediatric emergency departments”
Post docs/fellows/residents: Rebecca S. Zee, M.D., Ph.D., for “Implementation of the Accelerated Care of Torsion (ACT) pathway: a quality improvement initiative for testicular torsion”
Graduate students: Alysia Wiener, BS, for “Latency period in image-guided needle bone biopsy in children: a single center experience”

View images from the REW2019 award ceremony.

Urinary bacteria in spinal cord injury cases may tip balance toward UTIs

January 17, 2019

Patients with spinal cord injuries nearly universally have bacteria present in their urine regardless of whether they have a urinary tract infection.

The fallout from spinal cord injury doesn’t end with loss of mobility: Patients can have a range of other issues resulting from this complex problem, including loss of bladder control that can lead to urine retention. One of the most serious implications is urinary tract infections (UTIs), the most common cause of repeat hospitalization in people with spinal cord injuries, explains Hans G. Pohl, M.D., associate chief in the division of Urology at Children’s National Health System.

Diagnosing UTIs in people with spinal cord injuries is trickier than in people who are otherwise healthy, Dr. Pohl explains. Patients with spinal cord injuries nearly universally have bacteria present in their urine regardless of whether they have a UTI. It’s unclear whether these bacteria are innocent bystanders or precursors to UTIs in patients who don’t yet show symptoms. And although antibiotics can wipe out this bacterial population, these drugs can have undesirable side effects and frequent use can promote development of antibiotic-resistant bacteria.

Although clinical dogma has long promoted the idea that “healthy” urine is sterile, Dr. Pohl and colleagues have shown that a variety of bacteria live in urine, even in people without symptoms. These microorganisms, like the intestinal microbiome, live in harmony with their hosts and may even help promote health. However, it’s unclear what this urinary microbiome might look like for patients with spinal cord injury before, during and after UTIs.

To start investigating this question, Dr. Pohl and co-authors recently reported a case study they published online Sept. 21, 2018, in Spinal Cord Series and Cases. The case report about a 55-year-old man who had injured the thoracic segment of his spinal cord—about the level of the bottom of his shoulder blades—in a skiing accident when he was 19 was selected as “Editor’s Choice” for the journal’s October 2018 issue. The patient had a neurogenic bladder, which doesn’t function normally due to impaired communication with the spinal cord. To compensate for this loss of function, this patient needed to have urine removed every four to six hours by catheterization.

Over eight months Dr. Pohl, the study’s senior author, and colleagues collected 12 urine samples from this patient:

One was collected at a time the patient didn’t show any symptoms of a UTI
Nine were collected when the patient had UTI symptoms, such as bladder spasticity
Two samples were collected when the patient had finished antibiotic treatment for the UTI.

The researchers split each sample in half. One part was put through a standard urinalysis and culture, much like what patients with a suspected UTI would receive at the doctor’s office. The other part was analyzed using a technique that searched for genetic material to identify bacteria that might be present and to estimate their abundance.

The researchers found a variety of different bacteria present in these urine samples. Regardless of the patient’s health status and symptoms, the majority of these bacterial species are known to be pathogenic or potentially pathogenic. By contrast, this patient’s urine microbiome appeared to largely lack bacterial species known to be either neutral or with potentially probiotic properties, such as Lactobacillus.

All of the bacteria that grew in culture also were identified by their genetic material in the samples. However, genetic sequencing also identified a possible novel uropathogenic species called Burkholderia fungorum that didn’t grow in the lab in five of the samples. This bacterium is ubiquitous in the environment and has been identified in soil- and plant-based samples. It also has been discovered in the respiratory secretions of patients with cystic fibrosis, in patients with a heart condition called infectious endocarditis, in the vaginal microbiota of patients with bacterial vaginosis, and in the gut of patients with HIV who have low T-cell counts. Dr. Pohl says it’s unclear whether this species played an infectious role in this patient’s UTI or whether it’s just part of his normal urine flora.

“Consistent with our previous work, this case report demonstrates that rather than healthy urine being sterile, there is a diverse urine bacterial ecosystem during various states of health and disease,” Dr. Pohl says. “Rather than UTIs resulting from the growth or overgrowth of a single organism, it’s more likely that a change in the healthy balance of the urine ecosystem might cause these infections.”

By monitoring the relative abundance of different bacteria types present in the urine of patients with spinal cord injury and combining this information with a patient’s symptoms, Dr. Pohl says doctors may be able to make more accurate UTI diagnoses in this unique population.

In addition to Dr. Pohl, study co-authors include Marcos Pérez-Losada, Ljubica Caldovic, Ph.D., Bruce Sprague and Michael H. Hsieh, M.D., Children’s National; Emma Nally, Suzanne L. Groah and Inger Ljungberg, MedStar National Rehabilitation Hospital; and Neel J. Chandel, Montefiore Medical Center.

MRI and ultrasound imaging detect the spectrum of Zika’s impact

December 7, 2018

“A combination of prenatal MRI and US was able to detect Zika-related brain abnormalities during pregnancy, giving families timely information to prepare for the potential complex care needs of these infants,” says Sarah B. Mulkey, M.D., Ph.D.

Worldwide, thousands of babies have been born to mothers who were infected during pregnancy with Zika, a virus associated with neurological deficits, impaired vision and neurodevelopmental disabilities, among other birth defects. These birth defects are sometimes severe, causing lifelong disability. But they’re also relatively rare compared with the overall rates of infection.

Predicting how many Zika-exposed babies would experience neurological birth defects has been challenging.

However, an international study led by Children’s faculty suggests that ultrasound (US) imaging performed during pregnancy and after childbirth revealed most Zika-related brain abnormalities experienced by infants exposed to the Zika virus during pregnancy, according to a prospective cohort study published online Nov. 26, 2018, in JAMA Pediatrics. Some Zika-exposed infants whose imaging had been normal during pregnancy had mild brain abnormalities detected by US and magnetic resonance imaging (MRI) after they were born.

“A combination of prenatal MRI and US was able to detect Zika-related brain abnormalities during pregnancy, giving families timely information to prepare for the potential complex care needs of these infants,” says Sarah B. Mulkey, M.D., Ph.D., a fetal-neonatal neurologist at Children’s National Health System and the study’s lead author. “In our study, we detected mild brain abnormalities on postnatal neuroimaging for babies whose imaging was normal during pregnancy. Therefore, it is important for clinicians to continue to monitor brain development for Zika-exposed infants after birth.”

As of Nov. 20 2018, nearly 2,500 pregnant women in the U.S. had laboratory confirmed Zika infection, and about 2,400 of them had given birth, according to the Centers for Disease Control and Prevention (CDC). While more than 100 U.S. infants were born with Zika-associated birth defects, the vast majority of Zika-exposed U.S. infants were apparently normal at birth. The sequential neuroimaging study Dr. Mulkey leads seeks to determine the spectrum of brain findings in infants exposed to Zika in the womb using both US and MRI before and after birth.

The international research team enrolled 82 women in the study from June 15, 2016, through June 27, 2017. All of the women had been exposed to Zika during pregnancy; all but one experienced clinical symptoms by a mean gestational age of 8.2 weeks. Eighty of those women lived in or near Barranquilla, Colombia, and were exposed to Zika there. Two U.S. study participants were exposed to the primarily mosquito-borne illness during travel to Zika hot zones.

All women received fetal MRIs and US during the second and/or third trimester of pregnancy. After their infants were born, the children received brain MRI and cranial US. Blood samples from both mothers and babies were tested for Zika using polymerase chain reaction and serology.

Fetal MRI was able to discern Zika-related brain damage as early as 18 weeks gestation and picked up significant fetal brain abnormalities not fully appreciated in US imaging. In one case, the US remained normal while fetal MRI alone detected brain abnormalities. Three fetuses (4 percent) had severe fetal brain abnormalities consistent with Zika infection, including:

Two cases of heterotopias and malformations in cortical development, and
One case of parietal encephalocele, Chiari II malformation and microcephaly.

Seventy-five infants were born at term. One pregnancy was terminated at 23 weeks gestation due to the gravity of the fetal brain abnormalities. One fetus with normal imaging died during pregnancy. One newborn who was born with significant fetal brain abnormalities died at age 3 days.

Cranial US and brain MRI was performed on the majority of infants whose prenatal imaging had been normal. Seven of 53 (13 percent) Zika-exposed infants had mild brain abnormalities detected by MRI after birth. In contrast, postnatal cranial US was better at detecting changes of lenticulostriate vasculopathy, cysts within the brain’s choroid plexus (cells that produce cerebrospinal fluid), germinolytic/subependymal cysts and/or calcifications, which were seen in 21 of 57 (37 percent) infants.

“Sequential neuroimaging revealed that the majority of Zika-exposed fetuses had normal brain development. Tragically, in a small number of pregnancies, Zika-related brain abnormalities were quite severe,” Dr. Mulkey adds. “Our data support the CDC’s recommendation that cranial US be performed after Zika-exposed babies are born. In addition, there is clearly a need to follow these babies over time to gauge whether the brain anomalies we see in imaging affects language, motor and social skills.”

Companion editorial: Revealing the effects of Zika

In addition to Dr. Mulkey, study co-authors include Dorothy I. Bulas, M.D., Gilbert Vezina, M.D., Margarita Arroyave-Wessel, MPH, Stephanie Russo, B.S, Youssef A. Kousa, D.O, Ph.D., Roberta L. DeBiasi, M.D., MS, Senior Author Adré J. du Plessis, M.B.Ch.B., MPH, all of Children’s National; Christopher Swisher, BS, Georgetown University and Caitlin Cristante, BS, Loyola University, both of whose contributions included research performed at Children’s National; Yamil Fourzali, M.D., Armando Morales, M.D., both of Sabbag Radiologos; Liliana Encinales, M.D., Allied Research Society; Nelly Pacheco, Bacteriologa, Bio-Nep; Robert S. Lanciotti, Ph.D., Arbovirus Diseases Branch, Centers for Disease Control and Prevention; and Carlos Cure, M.D., BIOMELAB.

Research reported in this news release was supported by the IKARIA fund.

Phage therapy draws renewed interest to combat drug-resistant microbes

October 5, 2018

In the face of growing antibiotic resistance and few antibiotics in the development pipeline, phages are drawing renewed research interest as a potential silver bullet.

The married professors were spending their Thanksgiving holiday in Egypt when the husband, Thomas L. Patterson, Ph.D., got very sick very quickly, experiencing fever, nausea and a racing heartbeat. By the time Patterson was accurately diagnosed with a highly multi-drug resistant bacterial infection, he was near death. His wife, Steffanie Strathdee, Ph.D., promised to “leave no stone unturned.’”

What happened next is the ultimate infectious disease feel good story: Strathdee, part of an All-Star team of infectious disease experts and epidemiologists, concocted a cocktail of viruses that killed the superbug and saved Patterson’s life.

“He was going to die,” says Roberta L. DeBiasi, M.D., MS, chief of the Division of Pediatric Infectious Diseases at Children’s National Health System. “Because of her epidemiology background – and because she loves him – Patterson became the first patient successfully treated with bacteriophages.”

Dr. DeBiasi explains that all viruses take over cells and use their machinery for their own purposes. In order to escape, viruses blow up the cell. Bacteriophages are viruses that target bacteria, taking over their machinery and ultimately killing the bacterial host.

“Infection is a race between the body’s immune response and the bacteria replicating themselves,” she adds. “Bacteria have to continually replicate. If you knock out 90 percent of them with phage therapy, that gives the immune system a fighting chance to win the race.”

She was so inspired by the team’s ingenuity that DeBiasi, program vice-chair, invited them to recount the story during IDWeek2018, held Oct. 3 to Oct. 7, 2018, in San Francisco. During the closing plenary, Patterson, a professor of psychiatry, and Strathdee, associate dean of Global Health Sciences, will be joined by Robert T. “Chip” Schooley, M.D., (all of University of California, San Diego), to discuss the clinical aspects and efficacy of phage therapy.

About 50 years ago, the U.S. military had investigated leveraging phages but ultimately placed that research portfolio on the back burner. Now, in the face of growing antibiotic resistance and few experimental antibiotics in the development pipeline, phages are drawing renewed research interest as a potential silver bullet.

“The technology has been around for 50 years. We’re going back to old things because we’re so desperate,” Dr. DeBiasi adds.

The tricky thing with phages is that each bacterium needs its own tailored phage therapy.

Children’s National is working with Adaptive Phage Therapeutics, a company based in Gaithersburg, Maryland, that developed the phage used to save Patterson, in order to help build out that library of phages, each ready to be directed to do battle against a specific pathogen.

“We have been consultants to them to think about what would be a good clinical trial, particularly in a pediatric population,” Dr. DeBiasi says.

Children’s National has been collecting and sending isolates from patients with neurogenic bladder who experience urinary tract infections to shore up the phage library in anticipation of a clinical trial. The work builds on Children’s experience as the first center to use phage therapy in a pediatric patient, a 2-year-old who had multidrug-resistant Pseudomonas aeruginosa infection complicated by bacteremia/sepsis.

Detecting and treating dnDSA early preserves allograft function

February 5, 2018

Monitoring and treating de novo donor-specific antibodies (dnDSA) before they could cause graft damage helped to decrease dnDSA in a majority of pediatric kidney transplant recipients at Children National Health System and prevented graft failure in the first few years.

Development of de novo donor-specific antibodies (dnDSA) is known to cause graft failure. Therefore, a protocol aimed at prospective monitoring and treating dnDSA – before they can cause graft damage – was developed for kidney transplant recipients at Children National Health System. This helped to decrease dnDSA in 76 percent of pediatric patients and prevented graft failure in the first few years, indicates a longitudinal cohort study published online Jan. 22, 2018, in Pediatric Transplantation. However, the benefit of preserving function of transplanted kidneys came at a price: Heightened hospitalization rates for infection.

An estimated 20 percent to 30 percent of children develop dnDSA and many of these patients go on to develop allograft failure after three to six years, write the study authors.

Clinical signs of graft failure due to antibodies appear too late to safeguard long-term graft survival. According to the study authors, developing earlier methods to detect dnDSA offers the opportunity to intervene before irreversible graft injury occurs.

“Children’s National Health System instituted a routine protocol that standardizes monitoring and treatment of dnDSA,” says Asha Moudgil, M.D., FASN, associate chief of the Division of Nephrology at Children’s National and the study’s senior author. “We followed this protocol as we monitored and treated all children younger than 19 who received a kidney transplant at Children’s National from Jan. 1, 2008, to Dec. 31, 2013.”

After transplant, these children were monitored for development of dnDSA at six months and then yearly. Upon detection of DSA, these children underwent kidney biopsy to assess for acute rejection. Additionally, monitoring was intensified to every two months.

“Our patients did not have a statistically significant increase in graft loss or dysfunction, suggesting that early and targeted treatment of dnDSA may benefit patients,” says Asha Moudgil, M.D., FASN.

Sixty-seven of the 72 children who received kidney transplants during that six-year period were included in this retrospective analysis. Their mean age was 14.1 years. Acute cellular rejection was treated according to a prespecified protocol.

The team treated de novo DSA with high-dose intravenous immunoglobulin (IVIG) if antibody titers were low and added two doses of rituximab to that treatment regimen if antibody titers were high.
If either C1q binding of immunodominant DSA was present or C4d+ were seen on biopsy, six sessions of plasma exchange were added to the above protocol.
Kids who were resistant to such treatment approaches received an additional four doses of IVIG monthly.

Nearly 39 percent of the children developed dnDSA within a median of 1.36 years. Ten of these 26 children had increased creatinine, 12 had new onset proteinuria and six had newly diagnosed hypertension at the time the dnDSA was detected. The multivariate analysis found that the coefficient of variance of tacrolimus, which measures adherence to immunosuppressive drugs, was the only statistically significant predictor for developing dnDSA.

DSA-positive patients had a higher rate of admissions (1.23 hospital admissions for infectious- or immunosuppressive-related side effects per patient, compared with 0.59 hospital admissions for the DSA-negative patients), which the study team attributes to aggressive treatment of dnDSA.

“Our patients did not have a statistically significant increase in graft loss or dysfunction, suggesting that early and targeted treatment of dnDSA may benefit patients,” Dr. Moudgil adds. “There was a higher risk of treatment-related complications, however, and this risk must be balanced against the short-term benefit of prolonging allograft function.”

Study co-authors include Olga Charnaya, M.D., a Children’s fellow when the study was designed and the article was drafted, now at Johns Hopkins; and Children’s Nephrologist, Shamir Tuchman, M.D.

Tag Archive for: infection