Infectious Disease

Sarah Mulkey

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

Sarah Mulkey

“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:

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.

Deer tick

Lyme disease: When will pediatric symptoms resolve?

Deer tick

Over a 13-year period that began in 2004, cases of illness transmitted by ticks, mosquitoes and fleas have more than tripled, the CDC found.

The summer of 2018 was a bad summer for Lyme disease, the tick-borne disease that was first documented in the 1970s in the town of Lyme, Connecticut. While about 30,000 cases of this disease had been reported annually in recent years, studies suggest that the actual number of infections is around 10 times greater.

And according to a study published May 2018 by the Centers for Disease Control and Prevention (CDC), those case numbers may increase over time. Over a 13-year period that began in 2004, cases of illness transmitted by ticks, mosquitoes and fleas have more than tripled, the CDC found.

Lyme disease causes a host of uncomfortable symptoms, ranging from headache and neurological problems, heart problems and eye inflammation in earlier stages, and progressing to joint pain and arthritis in later stages. While it can be treated successfully with appropriate antibiotics, the timeframe for kids’ symptom resolution has been unclear.

A new study by researchers at Children’s National Health System shows that symptoms improve just days or weeks after starting antibiotic therapy for the vast majority of patients, with people whose symptoms had been present a briefer time improving the fastest.

“These findings offer a reassuring timeline for doctors, patients and their families about when patients with Lyme disease can expect to feel better,” says study Senior Author Roberta L. DeBiasi, M.D., MS, Children’s National’s chief of the Division of Pediatric Infectious Diseases and co-director of the Congenital Zika Virus Program. Dr. DeBiasi was recently appointed to serve on a 52-member Tick-Borne Disease Working Group established in 2018 by the Department of Health and Human Services.

Dr. DeBiasi and colleagues collected data retrospectively from the medical records of 78 patients who had been hospitalized at Children’s National for Lyme disease from 2008 to 2015. Each child, who was younger than 18 years old, had documented symptoms and lab tests conclusive for this disease.

Just under one-half had symptoms consistent with early-stage disease, such as:

  • A severe headache
  • Meningitis (inflammation of the membranes covering the brain)
  • Cranial nerve palsy (a nerve dysfunction that affects eye movement and can cause double vision)
  • Multiple erythema migrans rashes (the bulls-eye-shaped rash that’s a hallmark of Lyme disease) and
  • Pseudotumor cerebri (increased pressure inside the skull).

Just over one-half had symptoms consistent with late-stage disease, which mostly consisted of arthritis affecting the knees, along with the hips and elbows in some cases.

In the hospital, each patient was started on an antibiotic that can effectively treat Lyme, including doxycycline, cefotaxime or ceftriaxone, which they continued at home for the prescribed length of the course. The researchers then tracked how quickly the patients’ symptoms resolved.

They report online July 30, 2018, in the Journal of the Pediatric Infectious Diseases Society, that the time to symptom resolution for early stages of disease did not depend on the duration of symptoms prior to starting antibiotics. However, for later stages of disease, patients with longer duration of symptoms prior to starting treatment took longer for their symptoms to resolve.

For patients with early-stage disease, the most common symptom was headache; the median time to symptom resolution was just three days, no matter how long the headache had persisted before treatment started. However, for patients with late-stage Lyme disease, the median time to resolution was 18 days. However, the time depended largely on how long symptoms had persisted before patients began taking antibiotics. For example, patients who had experienced arthritis for less than one week had a shorter time to resolution than those who had arthritis for more than two weeks.

This finding is important, Dr. DeBiasi says, because it suggests that diagnosing Lyme disease earlier – and prescribing the appropriate therapy as soon as possible – can hasten recovery. The vast majority of patients in the study, she adds, eventually experienced full resolution of their symptoms, which should be comforting to families worried about whether their child will ever feel well again.

“We all want what patients and their families want: to feel better as quickly as possible,” Dr. DeBiasi says. “This study gives us valuable information about how soon that will happen given the duration of pediatric patients’ symptoms.”

Dr. DeBiasi and Children’s Psychologist Maureen Monaghan, Ph.D., are leading another Lyme study in collaboration with the National Institutes of Health/National Institute of Allergy and Infectious Diseases to evaluate symptom resolution, quality of life and neurocognitive outcomes in a larger group of pediatric patients with Lyme disease.

In addition to Dr. DeBiasi and Monaghan, Children’s co-authors include Lead Author Mattia E. Chason; Biostatistician Jichuan Wang, Ph.D.; and Yao Cheng.

Maureen E Lyon

Maureen E. Lyon, Ph.D., ABPP, lauded for outstanding excellence in patient-centered advance care planning

Maureen E Lyon

Maureen E. Lyon, Ph.D., a principal investigator at Children’s Center for Translational Science, will be honored with a “Recognition Award for Excellence and Innovation in Research” by Respecting Choices for outstanding excellence in patient-centered advance care planning and shared decision-making.

Respecting Choices will present the award on Oct. 26, 2018, during its “National Share the Experience Conference” in Bloomington, Minnesota.

Lyon’s expertise is in advance care planning and shared decision-making for children and adolescents with life-threatening illnesses and their families, a field that has transformed in recent decades in order to pave better paths forward for difficult but necessary conversations.

“It came from my clinical experience,” Lyon says. “In the early days of the human immunodeficiency virus (HIV) epidemic in the U.S., everything, absolutely everything, was done to keep the kids alive in the hopes that some new drug would come around the corner, and we could bring them back from the brink. I remember one of the young boys saying to his case manager that he didn’t want all of these interventions. But he hadn’t told his family.”

That young man’s eye-opening comments – and learning that Children’s National Health System had a policy that teenagers were to be included in conversations about their own advance care planning – inspired Lyon to conduct a series of surveys involving adolescents, families and clinicians.

“I remember sitting down with friends and saying ‘There must be a better way to do this. Everyone is afraid to broach the subject,’ ” Lyon recalls. So, she conducted surveys of all healthy kids coming through Children’s adolescent clinic and kids diagnosed with HIV, cancer and sickle cell disease.

“It turned out the kids did want to talk about it. That was the first thing. Families told us they wanted help breaking the ice. Physicians felt it wasn’t their role – many doctors felt their role was to save people – or, they didn’t have the training,” she says.

Through a series of focus groups with youths living with HIV, families and community members, Lyon adapted the adult-centric Respecting Choices model to create a three-session intervention to better meet the advance care planning needs of youths and adolescents living with HIV.

Lyon’s recent work includes a single-blinded, randomized study published Oct. 19, 2018, in Pediatrics that finds the more families understand the end-of-life treatment preferences expressed by adolescents living with HIV, the less likely these youth are to suffer HIV-related symptoms, compared with youths whose families do not understand their end-of-life care goals.

She also has adapted the Respecting Choices intervention to facilitate its use with children diagnosed with cancer. More recently, she has adapted the model for use by parents of children with rare diseases who cannot communicate on their own.

“For the other life-threatening health conditions, we worked to support adolescents in expressing their advance care planning choices in their own voices. With rare diseases, we’re shifting gears,” she adds.

Published research indicates a sizable proportion of pediatric patients who die in hospitals now have confirmed or suspected rare diseases, she says. During a pilot involving seven families, many parents multitasked during the conversations, taking pauses to attend to various alarms as they sounded, to complete regular feedings and to contend with their child’s petit mal seizures.

“The level of burden of taking care of these children with terminal illnesses was pretty overwhelming,” she says. “Still, families were not too burdened to participate in advance care planning, but first wanted to identify their priority palliative care needs and to develop a support plan to meet those needs. We also had more fathers involved.”

bacteriophage

Phage therapy draws renewed interest to combat drug-resistant microbes

bacteriophage

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.

Staphylococcus aureus

Understanding antibiotic resistance in patients with cystic fibrosis

Staphylococcus aureus

Patients with cystic fibrosis who carried antibiotic-resistant bacteria, such as Staphylococcus aureus, in their lungs had significantly lower microbial diversity and more aggressive disease, according to a small study published in Heliyon.

A defective gene causes thick, sticky mucus to build up in the lungs of patients with cystic fibrosis (CF). There, it traps bacteria, causing patients to develop frequent lung infections that progressively damage these vital organs and impair patients’ ability to breathe.

Most patients with this progressive genetic disorder die by the fourth decade of life. A key to helping patients live even that long – a vast improvement from an average lifespan of 10 years  just decades ago – is judicious use of antibiotics, explains Andrea Hahn, M.D., a pediatric infectious diseases specialist at Children’s National Health System.

But antibiotics are a double-edged sword, Dr. Hahn adds: Although they’re necessary to eradicate lung infections, repeated use of these drugs can lead to antibiotic resistance, making it tougher to treat future infections. Also, antibiotic use can kill the nonpathogenic bacteria living in the lungs as well. That decreases the diversity of the microbial community that resides in the lungs, a factor associated with disease progression. But how antibiotic resistance impacts the relationship between lung bacterial diversity and CF patients’ pulmonary function has been unknown.

Dr. Hahn and colleagues investigated this question in a small study that was published online Sept. 17, 2018, in Heliyon. Their findings suggest that the presence of multidrug resistant bacteria in the airways of patients with CF is associated with decreased microbial diversity and decreased pulmonary function.

In the study, the researchers recruited six patients with CF from Children’s National during well-child visits. During those appointments, the research team collected respiratory secretions from these volunteers. They collected more samples at subsequent visits, including:

  • When patients were admitted to the hospital for pulmonary exacerbations (periods when infections inflamed their airways, making it difficult to breathe);
  • Just after intravenous antibiotic courses to treat these infections; and
  • Thirty days after patients completed antibiotic therapy, when their lungs’ bacterial flora had some time to bounce back.

Over the 18-month study period, these patients made multiple visits for exacerbations and antibiotic treatments, leading to samples from 19 patient encounters overall.

The scientists then analyzed each sample in two different ways. They used some to grow cultures in petri dishes, the classic method that labs use to figure out which bacterial species are present and to determine which antibiotics are effective in tamping them down. They used another part of the sample to run genetic analyses that searched for antibiotic resistance genes. Both methods were necessary to gather a complete inventory of which antibiotic-resistant bacteria were present, Dr. Hahn explains.

“Laboratory cultures are designed to grow certain types of bacteria that we know are problematic, but they don’t show everything,” she says. “By genetically sequencing these samples, we can see everything that’s there.”

Their results revealed a host of bacterial species present in these patients’ airways, including methicillin-resistant Staphylococcus aureus, a notoriously hard-to-treat microbe. Patients who carried this or other antibiotic-resistant bacteria had significantly lower microbial diversity in their samples and more aggressive disease. Their samples also were more likely to contain bacteria of the genus Alcaligenes, whose role in CF is not yet known.

Although heavy antibiotic use probably contributed to both the antibiotic resistance and lowered microbial diversity, Dr. Hahn says, the answer isn’t to reduce use of these drugs: They’re necessary to help patients with CF recover after each bout with pulmonary exacerbations. Rather, she says, using methods beyond a simple lab culture can help doctors target infectious bacteria more selectively, perhaps avoiding collateral damage.

“We can’t stop using antibiotics,” she says, “but we can learn to use them better.”

In addition to Dr. Hahn, Children’s co-authors include Aszia Burrell; Hani Fanous; Hollis Chaney, M.D.; Iman Sami Zakhari, M.D.; Geovanny F. Perez, M.D.; Anastassios C. Koumbourlis, M.D., MPH; and Robert J. Freishtat, M.D., MPH; and Senior Author, Keith A. Crandall, of The George Washington University.

Financial support for the research described in this post was provided by the National Institutes of Health National Center for Advancing Translational Sciences under award number UL1TR000075 and the National Heart, Lung and Blood Institute under award number K12HL119994.

Natella Rakhamania

Natella Yurievna Rakhmanina named to regional HIV planning commission

Natella Rakhamania

Natella Yurievna Rakhmanina, M.D., Ph.D., FAAP, AAHIVS, director of Ryan White HIV Services at Children’s National Health System, was appointed a commissioner to the Washington, D.C., Regional Planning Commission on Health and HIV.

Dr. Rakhmanina will be among the District of Columbia board and commission appointees honored during a swearing-in ceremony on Sept. 17, 2018, at the Walter Washington Convention Center.

Looking back over the last decade, she says the District has made impressive progress in lowering the prevalence rate of human immunodeficiency virus (HIV), which in 2002 had 1,686 per 100,000 District residents diagnosed with AIDS.

“It was really high. I was stunned coming to clinic and seeing a large number of kids and adolescents in care and many suffering significant complications, as our treatment options were limited at the time,” she says.

Since that time, DC Health has made “incredible investments” and adopted innovative approaches, such as name-based reporting of HIV and a Red Carpet program, to ensure newly diagnosed people are quickly linked with care. As a proud partner of DC Health’s HIV/AIDS, Hepatitis, STD and TB Administration, Children’s National launched a campaign in 2009 to universally test adolescents for HIV in two pediatric emergency departments (ED), she says.

“All teenagers aged 13 and older who arrive for any medical diagnosis are offered an oral HIV test. Children’s National ED-based HIV screening program alone has tested 30,000 children at both of our emergency departments,” she says. “We’re still not at our goal. However, the prevalence of HIV had dropped to 1.9 percent in the latest department of health analysis. We are doing better. We have much fewer people dying from AIDS. We are diagnosing earlier.”

What’s more, trends in mother-to-child transmission, a major route of transmission for pediatric HIV, also have improved in D.C.

“In 2006, our maternal HIV transmission rates were among the highest in the nation. But, in 2013, 2014 and 2015 there were zero cases. We have seen some setbacks recently, however.  In 2016, there were three perinatally acquired cases and four in 2017, but these cases came out of the larger Metropolitan D.C. area,” she explains. “Every perinatally transmitted case for us is a red star. We work very closely with the regional departments of health. We really want to get back to zero cases of maternal transmission in the region.”

The regional planning commission meets several times per year to decide how to distribute federal funding in Washington and the Metropolitan D.C. area to support HIV prevention, diagnosis, treatment and care.

“My voice on the council is to make sure I speak up for services for mothers, children and adolescents,” Dr. Rakhmanina says. “The biggest challenge of HIV care remains treating children. There’s a good selection of medicines for adults, but not all are suited for kids. Young children in particular can’t be given one pill once a day. Really young children can’t swallow a pill. Using a liquid formulation, which kids prefer, may mean opening three different bottles twice daily and swallowing a liquid that often doesn’t taste good.”

Adolescents diagnosed with HIV also find medication adherence challenging, she says.

“At that age, they face a lot of challenges to self-acceptance and disease management, in part, because it’s not a physical disability. A young person with HIV may not feel anything,” she says. “They struggle with staying on daily medications. Many of them tell us they don’t want to think about HIV and face stigma.”

Another ongoing challenge is ensuring moms living with HIV remain on medicines after they’ve given birth.

“They’re tremendously committed to continuing treatment while pregnant: Treatment means their babies are born free of HIV,” she says. “That is a great success. Once the baby is born, many times the women bring their babies to be tested, but the woman’s own health becomes less of a priority. We see a drop in adherence once they have the baby.”

By serving on the commission, Dr. Rakhmanina aims to push to extend Children’s commitment to excellence beyond its walls.

Monika Goyal

Missed opportunities for STI screening in the ED

Monika Goyal

Children’s researchers led by Monika K. Goyal, M.D., M.S.C.E., find that even though young women with pelvic inflammatory disease (PID) are at increased risk for being infected with syphilis and human immunodeficiency virus (HIV), few adolescent females diagnosed with PID in U.S. pediatric emergency departments undergo laboratory tests for HIV or syphilis.

Sexually transmitted infections (STIs) are on the rise in the U.S., reaching unprecedented highs in recent years for the three most common STIs reported in the nation: chlamydia, gonorrhea and syphilis. Nearly half of the 20 million new STI cases each year are in adolescents aged 15 to 24, according to the Department of Health & Human Services. In particular, about two in five sexually active teen girls has an STI.

These infections can be far more than an embarrassing nuisance; some can cause lifelong infertility. According to the Centers for Disease Control and Prevention, undiagnosed STIs cause infertility in more than 20,000 women each year.

A new retrospective cohort study led by researchers at Children’s National Health System and published online July 24, 2018, in Pediatrics shines a stark spotlight on missed opportunities for diagnosis. Researchers found that even though young women with pelvic inflammatory disease (PID) are at increased risk for also being infected with syphilis and human immunodeficiency virus (HIV), few adolescent females diagnosed with PID in U.S. pediatric emergency departments (ED) undergo laboratory tests for HIV or syphilis.

A team of Children’s researchers reviewed de-identified data from the Pediatric Health Information System, a database that aggregates encounter-level data from 48 children’s hospitals across the nation. From 2010 through 2015, there were 10,698 diagnosed cases of PID among young women aged 12 to 21. Although HIV and syphilis screening rates increased over the study period, just 27.7 percent of these women underwent syphilis screening, 22 percent were screened for HIV, and only 18.4 percent underwent lab testing for both HIV and syphilis.

Screening rates varied dramatically by hospital, with some facilities screening just 2 percent of high-risk young women while others tested more than 60 percent.

HIV screening was more likely to occur among:

  • Women admitted to the hospital, compared with those discharged from the ED (adjusted odds ratio [aOR] of 7.0)
  • Uninsured women, compared with women with private insurance (1.6 aOR)
  • Non-Latino African American women, compared with non-Latino white women (1.4 aOR)
  • Women seen at small hospitals with fewer than 300 beds (1.4 aOR)
  • Women with public insurance compared with women with private insurance (1.3 aOR)
  • 12-year-olds to 16-year-olds, compared with older adolescents (1.2 aOR)

Syphilis screening was more likely to occur for:

  • Women admitted to the hospital (4.6 aOR)
  • Non-Latino African American women (1.8 aOR)
  • Uninsured women (1.6 aOR)
  • Women with public insurance (1.4 aOR)
  • 12-year-olds to 16-year-olds (1.1 aOR)

“We know that 20 percent of the nearly 1 million cases of PID that are diagnosed each year occur in young women, with the majority of diagnoses made in EDs. It is encouraging that HIV and syphilis screening rates for women with PID increased over the study period. However, our findings point to missed opportunities to safeguard young women’s reproductive health,” says Monika K. Goyal, M.D., M.S.C.E., assistant professor of Pediatrics and Emergency Medicine and the study’s senior author. “Such discrepancies in screening across the 48 hospitals we studied underscore the need for a standardized approach to sexually transmitted infection (STI) screening.”

Untreated STIs can cause PID, an infection of a woman’s reproductive organs that can complicate her ability to get pregnant and also can cause infertility. Since 2006, the Centers for Disease Control and Prevention (CDC) has recommended that all women diagnosed with PID be tested for HIV. The CDC’s treatment guidelines also recommend screening people at high risk for syphilis.

“Syphilis infection rates have steadily increased each year, and it is now most prevalent among young adults,” Dr. Goyal says. “Future research should examine how STI screening can be improved in emergency departments, especially since adolescents at high risk for STIs often access health care through EDs. We also should explore innovative approaches, including electronic alerts and shared decision-making to boost STI screening rates for young women.”

In addition to Dr. Goyal, Children’s study co-authors include Lead Author, Amanda Jichlinski, M.D.; and co-authors, Gia Badolato, M.P.H., and William Pastor, M.A., M.P.H.

Research reported in this news release was supported by the National Institute of Child Health and Human Development under K23 award number HD070910.

Making the grade: Children’s National is nation’s Top 5 children’s hospital

Children’s National rose in rankings to become the nation’s Top 5 children’s hospital according to the 2018-19 Best Children’s Hospitals Honor Roll released June 26, 2018, by U.S. News & World Report. Additionally, for the second straight year, Children’s Neonatology division led by Billie Lou Short, M.D., ranked No. 1 among 50 neonatal intensive care units ranked across the nation.

Children’s National also ranked in the Top 10 in six additional services:

For the eighth year running, Children’s National ranked in all 10 specialty services, which underscores its unwavering commitment to excellence, continuous quality improvement and unmatched pediatric expertise throughout the organization.

“It’s a distinct honor for Children’s physicians, nurses and employees to be recognized as the nation’s Top 5 pediatric hospital. Children’s National provides the nation’s best care for kids and our dedicated physicians, neonatologists, surgeons, neuroscientists and other specialists, nurses and other clinical support teams are the reason why,” says Kurt Newman, M.D., Children’s President and CEO. “All of the Children’s staff is committed to ensuring that our kids and families enjoy the very best health outcomes today and for the rest of their lives.”

The excellence of Children’s care is made possible by our research insights and clinical innovations. In addition to being named to the U.S. News Honor Roll, a distinction awarded to just 10 children’s centers around the nation, Children’s National is a two-time Magnet® designated hospital for excellence in nursing and is a Leapfrog Group Top Hospital. Children’s ranks seventh among pediatric hospitals in funding from the National Institutes of Health, with a combined $40 million in direct and indirect funding, and transfers the latest research insights from the bench to patients’ bedsides.

“The 10 pediatric centers on this year’s Best Children’s Hospitals Honor Roll deliver exceptional care across a range of specialties and deserve to be highlighted,” says Ben Harder, chief of health analysis at U.S. News. “Day after day, these hospitals provide state-of-the-art medical expertise to children with complex conditions. Their U.S. News’ rankings reflect their commitment to providing high-quality care.”

The 12th annual rankings recognize the top 50 pediatric facilities across the U.S. in 10 pediatric specialties: cancer, cardiology and heart surgery, diabetes and endocrinology, gastroenterology and gastrointestinal surgery, neonatology, nephrology, neurology and neurosurgery, orthopedics, pulmonology and urology. Hospitals received points for being ranked in a specialty, and higher-ranking hospitals receive more points. The Best Children’s Hospitals Honor Roll recognizes the 10 hospitals that received the most points overall.

This year’s rankings will be published in the U.S. News & World Report’s “Best Hospitals 2019” guidebook, available for purchase in late September.

Schistosoma haematobium egg

For hemorrhagic cystitis, harnessing the power of a parasite

Schistosoma haematobium egg

“Urogenital Schistosoma infestation, which is caused by S. haematobium, also causes hemorrhagic cystitis, likely by triggering inflammation when the parasite’s eggs are deposited in the bladder wall or as eggs pass from the bladder into the urinary stream. S. haematobium eggs secrete proteins, including IPSE, that ensure human hosts are not so sickened that they succumb to hemorrhagic cystitis,” says Michael H. Hsieh, M.D., Ph.D.

Every year, hundreds of thousands of U.S. patients – and even more throughout the world – are prescribed cyclophosphamide or ifosfamide. These two chemotherapy drugs can be life-saving for a wide range of pediatric cancers, including leukemias and cancers of the eyes and nerves. However, these therapies come with a serious side effect: Both cause hemorrhagic cystitis in up to 40 percent of patients. This debilitating condition is characterized by severe inflammation in the bladder that can cause tremendous pain, life-threatening bleeding, and frequent and urgent urination.

Infection with a parasitic worm called Schistosoma haematobium also causes hemorrhagic cystitis, but this organism has a fail-safe: To keep its host alive, the parasite secretes a protein that suppresses inflammation and the associated pain and bleeding.

In a new study, a Children’s-led research team harnessed this protein to serve as a new therapy for chemotherapy-induced hemorrhagic cystitis.

“Urogenital Schistosoma infestation, which is caused by S. haematobium, also causes hemorrhagic cystitis, likely by triggering inflammation when the parasite’s eggs are deposited in the bladder wall or as eggs pass from the bladder into the urinary stream. S. haematobium eggs secrete proteins, including IPSE, that ensure human hosts are not so sickened that they succumb to hemorrhagic cystitis,” says Michael H. Hsieh, M.D., Ph.D., senior author of the study published April 3, 2018, by The FASEB Journal. “This work in an experimental model is the first published report of exploiting an uropathogen-derived host modulatory molecule in a clinically relevant model of bladder disease, and it points to the potential utility of this as an alternate treatment approach.”

S. mansoni IPSE binds to Immunoglobulin E (IgE), an antibody produced by the immune system that is expressed on the surface of basophils, a type of immune cell; and mast cells, another immune cell that mediates inflammation; and sequesters chemokines, signaling proteins that alert white cells to infection sites. The team produced an ortholog of the uropathogen-derived protein. A single IV dose proved superior to multiple doses of 2-Mercaptoethane sulfonate sodium (MESNA), the current standard of care, in suppressing chemotherapy-induced bladder hemorrhaging in an experimental model. It was equally potent as MESNA in dampening chemotherapy-induced pain, the research team finds.

“The current array of medicines we use to treat hemorrhagic cystitis all have shortcomings, so there is a definite need for novel therapeutic options,” says Dr. Hsieh, a Children’s National Health System urologist. “And other ongoing research projects have the potential to further expand patients’ treatment options by leveraging other urogenital parasite-derived, immune-modulating molecules to treat inflammatory bowel diseases and autoimmune disorders.”

Future research will aim to describe the precise molecular mechanisms of action, as well as to generate other orthologs that boost efficacy while reducing side effects.

In addition to Dr. Hsieh, Children’s study co-authors include Lead Author, Evaristus C. Mbanefo; Loc Le and Luke F. Pennington; Justin I. Odegaard and Theodore S. Jardetzky, Stanford University; Abdulaziz Alouffi, King Abdulaziz City for Science and Technology; and Franco H. Falcone, University of Nottingham.

Financial support for this research was provided by National Institutes of Health under award number RO1-DK113504.

Staphylococcus

How our bladder’s microbiota affect health

Staphylococcus

The presence of bacteria such as Staphylococcus in the urine is linked to the incidence and severity of urge urinary incontinence as well as treatment success.

About half of the cells in our bodies aren’t really “ours” at all. They’re the microbiota: The vast array of microorganisms that live in our gut, skin, oral cavity and other places. Decades ago, researchers thought that these organisms simply happened to colonize these areas, playing only a tangential role in health, for example, helping to break down food in the intestines or causing cavities. More recent work has revealed the incredibly complex role they play in diseases ranging from diabetes and schizophrenia.

The bladder is no exception. Just a single decade ago, the bladder was thought to be a sterile environment. But that view has shifted radically, with more sensitive cultivation methods and precise 16S rRNA gene-sequencing techniques revealing a significant bladder microbiome that could have an enormous impact on pediatric urologic diseases. These findings have opened brand new fields of research aimed at clarifying the role that the bladder’s microbiome plays in common urological diseases that affect children, according to a review article published online Feb. 22, 2018, by Current Urology Reports.

“There is a growing appreciation for the role of diverse bacteria in contributing to improved health as well as triggering disease processes or exacerbating illness,” says Michael H. Hsieh, M.D., Ph.D., director of the Clinic for Adolescent and Adult Pediatric Onset Urology (CAPITUL) at Children’s National Health System and study senior author. “Already, we know that probiotics and dietary modifications have the potential to play powerful roles in preventing urinary diseases that commonly occur among pediatric patients,” Dr. Hsieh says. This underscores the importance of conducting even more studies to improve our understanding and to identify new therapies for health conditions that resist current treatment options.”

The review conducted by Dr. Hsieh and co-authors highlights the effects of the microbiome on a number of urologic diseases that affect children, including:

  • Urinary tract infection A number of studies point to the association between decreased microbial diversity and the incidence of what is commonly called urinary tract infection (UTI) or “dysbiosis.” This relationship suggests that using probiotics to replace or supplement antibiotics could favorably alter the urinary microbiome. Future research will focus on the pathophysiological role of the microbiome to determine whether it can be manipulated to prevent or treat UTIs.
  • Urge urinary incontinence While data vary by study, the presence of bacteria in the urine, especially certain bacterial species – such as Gardnerella, Staphylococcus, Streptococcus, Actinomyces, Aerococcus, Corynebacterium and Oligella – are linked to the incidence and severity of urge urinary incontinence (UUI) as well as treatment success. Most studies find an association between greater genitourinary biodiversity and reduced incidence and lessened severity of UUI as well as improved treatment response. Future research will focus on further clarifying this relationship.
  • Urolithiasis Calcium oxalate stones, the most common type of kidney stone, have a microbiome that differs from the urinary microbiome leading researchers to question whether the stone’s own bacterial makeup could help to predict recurrence of future kidney stones. What’s more, Oxalobacter formigenes, a gram-negative bacterium, lowers oxalate levels in the blood and are associated with a 70 percent reduction in the risk of kidney stones forming. In an experimental model, fecal transplants with the full microbiome represented had a pronounced and persistent effect on oxalate production. Patients who receive some antibiotics often have reduced rates of formigenes colonization. However, the bacteria are resistant to amoxicillin, augmentin, ceftriaxone and vancomycin, which could point to preferential use of these antibiotics to stave off disease and ward off kidney stone formation.

Additional authors include Daniel Gerber, study lead author, The Georgetown University School of Medicine and Health Sciences; and Catherine Forster, M.D., study co-author, Children’s National.

Presidnet's Award for Innovation in Research

President’s Award highlights innovative work by early-career researchers

Presidnet's Award for Innovation in Research

As part of Research and Education Week 2018, two Presidential awardees were recognized for their research contributions, Catherine “Katie” Forster, M.D., M.S., and Nathan Anthony Smith, Ph.D.

Catherine “Katie” Forster, M.D., M.S., and Nathan Anthony Smith, Ph.D., received the President’s Award for Innovation in Research honoring their respective research efforts to explore an understudied part of the microbiome and to shed light on an underappreciated player in nerve cell communication.

Drs. Forster and Smith received their awards April 19, 2018, the penultimate day of Research and Education Week 2018, an annual celebration of the excellence in research, education, innovation and scholarship that takes place at Children’s National Health System. This year marks the fifth time the President’s Award honor has been bestowed to Children’s faculty.

Dr. Forster’s work focuses on preventing pediatric urinary tract infections (UTIs). Frequently, children diagnosed with illnesses like spina bifida have difficulty urinating on their own, and they often develop UTIs. These repeated infections are frequently treated with antibiotics which, in turn, can lead to the child developing antibiotic-resistant organisms.

“The majority of the time if you culture these children, you’ll grow something. In a healthy child, that culture would indicate a UTI,” Dr. Forster says. “Children with neurogenic bladder, however, may test positive for bacteria that simply look suspect but are not causing infection. Ultimately, we’re looking for better ways to diagnose UTI at the point of care to better personalize antibiotic treatment and limit prescriptions for children who do not truly need them.”

Powered by new sequencing techniques, a research group that includes Dr. Forster discovered that the human bladder hosts a significant microbiome, a diverse bacterial community unique to the bladder. Dr. Forster’s research will continue to characterize that microbiome to determine how that bacterial community evolves over time and whether those changes are predictable enough to intervene and prevent UTIs.

“Which genes are upregulated in Escherichia coli and the epithelium, and which genes are upregulated by both in response to each other? That can help us understand whether genes being upregulated are pathogenic,” she adds. “It’s a novel and exciting research area with significant public health implications.”

Smith’s work focuses on the role of astrocytes, specialized star-shaped glial cells, in modulating synaptic plasticity via norepinephrine. Conventional thinking describes astrocytes as support cells but, according to Smith, astrocytes are turning out to be more instrumental.

Norepinephrine, a neurotransmitter that plays an essential role in attention and focus, is released by a process known as volume transmission, which is a widespread release of a neurotransmitter at once, says Smith, a principal investigator in Children’s Center for Neuroscience Research. Astrocytes, which outnumber neurons in the brain, are strategically and anatomically located to receive this diffuse input and translate it into action to modulate neural networks.

“We hypothesize that astrocytes are integral, functional partners with norepinephrine in modulating cortical networks,” Smith adds. “Since astrocytes and norepinephrine have been implicated in many central nervous system functions, including learning and attention, it is critical to define mechanistically how astrocytes and norepinephrine work together to influence neural networks. This knowledge also will be important for the development of novel therapeutics to treat diseases such as attention deficit hyperactivity disorder and epilepsy.”

ER Nurse

An unexpected discovery in a central line

ER Nurse

About a year and a half ago, a 6-year-old boy arrived at Children’s Emergency Department after accidently removing his own gastrointestinal feeding tube. He wasn’t a stranger to Children’s National Health System: This young patient had spent plenty of time at the hospital since birth. Diagnosed in infancy with an intestinal pseudo-obstruction, a rare condition in which his bowels acted as if there were a blockage even though one was not present, parts of his intestine died and had been removed through multiple surgeries.

Because of this issue and associated health problems, at 4 years old he had a central line placed in a large vein that leads to his heart. That replaced other central lines placed in his neck earlier after those repeatedly broke. This latest central line in his chest als0 had frequent breaks. It also had become infected with multidrug-resistant Klebsiella bacteria two years before he was treated at Children’s National for inadvertently removing his feeding tube.

On that day, he seemed otherwise well. His exam was relatively unremarkable, except for a small leak in his central line and a slight fever. Those findings triggered cultures taken both from blood flowing through his central line and the surrounding skin.

“No one expected him to grow anything from these cultures, especially from a child who looked so healthy,” explains Madan Kumar, a fellow in Children’s division of Pediatric Infectious Disease and a member of the child’s care team. But a mold grew prolifically. Further investigation from a sample sent to the National Institutes of Health showed that it was a relatively new species known as Mucor velutinosus.

Because such an infection had never been reported in a child whose immune system wasn’t extremely compromised from cancer, Kumar and team decided to publish a case report. The study appeared online Jan. 24, 2018, in the Journal of the Pediatric Infectious Diseases Society.

Kumar notes that this patient faced myriad challenges. Not only did he have a central line, but the line also had numerous problems, necessitating fixes that could increase the chance of infection. Additionally, because of his intestinal issues, he had a chronic problem with malabsorption of nutrients. Patients with this issue often are treated liberally with antibiotics. Although this intervention can kill “bad” bacteria that can cause an infection, they also knock out “good” bacteria that keep other microorganisms – like fungi – in check. On top of all of this, the patient was receiving a nutrient-rich formula in his central line to boost his caloric intake, yet another factor associated with infections.

Patients who develop this specific fungal infection are overwhelmingly adults who are immunocompromised, Kumar explains, including those with diabetes, transplant recipients, patients with cancer and those who have abnormally low concentrations of immune cells called neutrophils in their blood. The only children who tend to get this infection are preterm infants of very low birth weight who haven’t yet developed a robust immune response.

Because there was only one other published case report about a child with M. velutinosus – a 1-year-old with brain cancer who had undergone a bone marrow transplant – Kumar notes that he and colleagues were at a loss as to how best to treat their patient. “There’s a paucity of literature on what to do in a case like this,” he says.

Fortunately, the treatment they selected was successful. As soon as the cultures came back positive for this mold, the patient went on a three-week course of an antifungal drug known as amphotericin B. Surgeons also removed his infected central line and placed a new one. These efforts cured the patient’s infection and prevented it from spreading and potentially causing the multi-organ failure associated with these types of infections.

This case taught Kumar and colleagues quite a bit – knowledge that they wanted to share by publishing the case report. For example, it reinforces the importance of central line care. It also highlights the value of thoroughly investigating potential problems in a patient with risk factors, even one who appears otherwise healthy.

Finally, Kumar adds, the case emphasizes the importance of good antibiotic stewardship, which can help prevent patients from developing sometimes deadly secondary infections like this one. “This is not an organism that you see growing in a 6-year-old very often,” he says. “The fact that we saw it here speaks to the need to be judicious with broad-spectrum antibiotics so that we have a number of therapeutic options should we see unusual cases like this one.”

Sarah Mulkey

MRI finds novel brain defects in Zika-exposed newborns

Sarah Mulkey

“Imaging is constantly helping us make new discoveries with this virus, and in these two cases we found things that had not been previously described,” says Sarah Mulkey, M.D., Ph.D.

Magnetic resonance imaging (MRI) has identified two brain abnormalities never before reported in newborns with prenatal exposure to the Zika virus. Children’s National Health System researchers reported these findings from a study of more than 70 fetuses or newborns with Zika exposure in utero. The study was published in the January 2018 edition of Pediatric Neurology.

The two novel defects – cranial nerve enhancement and cerebral infarction – may join the growing list of neurological findings associated with congenital Zika infection.

“Imaging is constantly helping us make new discoveries with this virus, and in these two cases we found things that had not been previously described,” says Sarah Mulkey, M.D., Ph.D., the study’s lead author and a fetal-neonatal neurologist at Children’s National. Dr. Mulkey works in Children’s Congenital Zika Virus Program, one of the nation’s first comprehensive, dedicated Zika programs.

The research team recommends that postnatal brain MRI be considered in addition to ultrasound for newborns exposed to Zika in utero. “Brain MRI can be performed in the newborn often without sedation and provides an opportunity to look for brain abnormalities we might not catch otherwise – or might not detect until much later,” says Dr. Mulkey.

Birth defects are seen in 6 to 11 percent of pregnancies affected by Zika, and some of the neurological complications in infants are not apparent until well after birth.

Of the two infants in which the new abnormalities were observed, both had normal head size at birth. Neither had smaller-than-normal head size (microcephaly), one of the more severe effects associated with congenital Zika syndrome.

One infant had a normal neurological evaluation at 2 days of age. However, a brain MRI conducted the following day, using gadolinium contrast due to concern of infection, showed enhancement of multiple cranial nerves. “Nerve root enhancement is very rare in a newborn and had not been described with Zika before,” Dr. Mulkey says. “Yet, there was no neurological deficit that we could identify by physical exam.”

The research team acknowledges that the clinical significance of this finding is not yet known.

In the second patient, brain MRI conducted without contrast at 16 days of age revealed a small area consistent with chronic infarction (ischemic stroke) that likely occurred during the third trimester.

“We followed the mother throughout her pregnancy, and both MRI and ultrasound imaging were normal at 28 weeks gestation,” Dr. Mulkey says. “A postnatal ultrasound was also normal, but the postnatal MRI showed a stroke that had occurred at least one month prior to the MRI and after the last fetal study.”

She adds: “This is the first published report of fetal stroke associated with Zika infection, and it may add to our knowledge of what can occur with congenital Zika infection.”

Unlike most congenital infections, Zika virus does not appear to cause viral-induced placental inflammation, which can lead to fetal stroke. So, the authors say they cannot be sure that congenital Zika contributed to the infarct in this case. However, they write, “Given the relatively low incidence of perinatal ischemic infarct and the lack of other maternal- or birth-related risk factors for this patient, Zika infection is considered a possible etiology.”

In both patients, neonatal brain MRI identified subclinical findings that had not previously been described as part of congenital Zika syndrome. As the body of evidence about the Zika virus has grown, the spectrum of associated brain abnormalities has expanded to include considerably more findings than isolated microcephaly.

Data gathered in 2017 from the Centers for Disease Control and Prevention’s Zika pregnancy and infant registry indicates that 25 percent of eligible U.S. infants receive recommended postnatal imaging. Dr. Mulkey said this represents many possible missed opportunities for earlier identification of brain abnormalities.

“Brain MRI should be considered in all newborns exposed to Zika virus in utero, even in the presence of normal birth head circumference, normal cranial ultrasound and normal fetal imaging,” she says. “In both of these patients, the changes we observed were not evident on cranial ultrasound or on fetal MRI and fetal ultrasound.”

In addition to Dr. Mulkey, Children’s co-authors include L. Gilbert Vezina, M.D., Neuroradiology Program director; Dorothy I. Bulas, M.D., chief of Diagnostic Imaging and Radiology; Zarir Khademian, M.D., radiologist; Anna Blask, M.D., radiologist; Youssef A. Kousa, M.S., D.O., Ph.D., child neurology fellow; Lindsay Pesacreta, FNP; Adré  J. du Plessis, M.B.Ch.B., M.P.H., Fetal Medicine Institute director; and Roberta L. DeBiasi, M.D., M.S., senior author and Pediatric Infectious Disease division chief; and Caitlin Cristante, B.S.

Financial support for this research was provided by the Thrasher Research Fund.

Lawrence D'Angelo

Being a young parent while also HIV positive

Lawrence D'Angelo

“We realize that at some point in time, these patients will have to transition their care to an adult setting, and they will confront a different kind of health system,” says Lawrence D’Angelo, M.D., M.P.H. “We want to make sure all of their providers will be able to help them advocate for themselves and for their children.”

By the time the human immunodeficiency virus (HIV) – the virus that causes AIDS – first came to the public consciousness in the 1980s, it was clear that infected pregnant mothers readily pass it to their babies. For those infected babies to eventually have their own children was inconceivable then, says Lawrence J. D’Angelo, M.D., M.P.H., adolescent medicine specialist at Children’s National Health System. Before the advent of antiretroviral therapy, AIDS was universally fatal.

Now, about 22 percent of young adults with HIV have lived with this disease their entire lives. And like many people this age, they’re exploring romantic relationships, sex and – for some – parenthood. This unexpected turn of events, Dr. D’Angelo explains, has left many health care providers unprepared.

“We never expected that these individuals would live to reach early adulthood, so we certainly didn’t expect them to be involved in parenting,” he says. “We have no real knowledge of what to expect from them or how best to support them because we don’t understand what they’re going through.”

To learn more about these young parents living with perinatally acquired HIV (PHIV), Dr. D’Angelo worked with Cynthia Fair, professor of human services studies and public health studies coordinator at Elon University. The two conducted a qualitative assessment of parents with PHIV. After recruiting 17 individuals who fit this description directly from Dr. D’Angelo’s practice, interviewers on the research team sat down with study participants to have a conversation about what it was like to parent while also being HIV positive. They asked standard questions, such as: What do you think makes a good parent? And, describe your relationship with your parents or caregivers. How does this relate, if at all, to your views on parenthood?

The team then transcribed these interviews and fed the text into a qualitative analysis program. With the aid of this software, and their own manual analysis, the researchers found several themes emerge from the conversations.

About 90 percent of the interviews focused on challenges universal to nearly every parent: Worries about a baby taking a bottle or sleeping through the night, struggles with discipline, concerns about money. “For the most part, these are young parents with a chronic illness just trying to be good parents,” says Fair, lead author of the study published Nov. 1, 2017 in AIDS Patient Care and STDs.

However, she adds, HIV inserts an added layer of complexity. Many of the parents said they felt deprived of the opportunity to enjoy lives as long and healthy as their peers. Consequently, having a child carried a sense of pressure to accomplish more in life for their children and to leave a positive legacy. Some worried that their own HIV status would stigmatize their children and that people outside their families would automatically assume their children were HIV positive when they weren’t.

All but one parent in the study had a child who was HIV negative, but even those children require regular testing to make sure they maintain that status. Parents with infants prescribed preventive protocols spoke about the exhaustion of having to deliver prophylactic medicines around the clock. The sole parent in the study with an HIV-positive child was separated from the baby’s father; she talked about the stress of not knowing whether her baby was receiving the necessary medicines to stay healthy when the child wasn’t with her.

These young parents also spoke with interviewers about the role their own pediatric care providers played in helping them make the transition to parenthood. For example, social workers on one study participant’s care team stepped in when she had nowhere to live, finding her an appropriate shelter. Another talked about how her desire to be a good parent was strongly influenced by the care she was given by her medical providers growing up. Many of the study participants had lost one or both parents to HIV or had absentee parents due to incarceration or other causes, says Fair, making their relationships with their medical team one of the few constants they could count on.

That’s why helping care providers develop a deep understanding of the perspectives of PHIV parents is even more important, particularly as these individuals move from pediatric to adult care settings, says Dr. D’Angelo, the study’s senior author and director of the Youth Pride and Burgess Clinics at Children’s National.

“We realize that at some point in time, these patients will have to transition their care to an adult setting, and they will confront a different kind of health system,” he says. “We want to make sure all of their providers will be able to help them advocate for themselves and for their children.”

Larry D'Angelo SAMH award

Larry D’Angelo, M.D., M.P.H., receives the Society for Adolescent Health and Medicine’s 2018 Outstanding Achievement Award

Larry D'Angelo SAMH award

Larry D’Angelo, M.D., M.P.H., emeritus Chief of the Division of Adolescent and Young Adult Medicine  at Children’s National Health System is being honored by the Society for Adolescent Health and Medicine (SAHM) with their most prestigious award, the 2018 Outstanding Achievement in Adolescent Health and Medicine.

The award acknowledges Dr. D’Angelo’s career-long dedication to adolescents and adolescent health care. Dr. D’Angelo is a pioneer in the care of and research for human immunodeficiency virus (HIV) infected patients, spending the past 35 years working to treat youth and adults with HIV/AIDS in the Washington area. As part of his work, Dr. D’Angelo founded and directed the Burgess Clinic for HIV-infected adolescents at Children’s National, the Youth Pride Clinic for LGBTQ health at Children’s National and the community-based organization, Metro TeenAIDS, currently part of the Whitman Walker Clinic.

Dr. D’Angelo was presented the award on March 15, 2018 at the SAHM’s Annual Meeting in Seattle.

“This is a tremendous honor that serves to validate not me and my work, but the collective efforts of everyone I’ve worked with here at Children’s National. I couldn’t have achieved anything without those in my Division nor without my colleagues across the institution.” Dr. D’Angelo says.

Dr. D’Angelo, an internationally recognized expert in adolescents and adolescent health care, is also emeritus executive director for The Diana L. and Stephen A. Goldberg Center for Community Pediatric Health and a senior scientist with the District of Columbia Center for AIDS Research’s Clinical and Population Sciences Core.  His academic appointments include professor Pediatrics, Medicine, Epidemiology, and Prevention and Community Health at The George Washington University.

Electronic medical record on tablet

Children’s National submissions make hackathon finals

Electronic medical record on tablet

This April, the Clinical and Translational Science Institute at Children’s National (CTSI-CN) and The George Washington University (GW) will hold their 2nd Annual Medical and Health App Development Workshop. Of the 10 application (app) ideas selected for further development at the hackathon workshop, five were submitted by clinicians and researchers from Children’s National.

The purpose of the half-day hackathon is to develop the requirements and prototype user interface for 10 medical software applications that were selected from ideas submitted late in 2017. While idea submissions were not restricted, the sponsors suggested that they lead to useful medical software applications.

The following five app ideas from Children’s National were selected for the workshop:

  • A patient/parent decision tool that could use a series of questions to determine if the patient should go to the Emergency Department or to their primary care provider; submitted by Sephora Morrison, M.D., and Ankoor Shah, M.D.
  • The Online Treatment Recovery Assistance for Concussion in Kids (OnTRACK) smartphone application could guide children/adolescents and their families in the treatment of their concussion in concert with their health care provider; submitted by Gerard Gioia, Ph.D.
  • A genetic counseling app that would provide a reputable, easily accessible bank of counseling videos for a variety of topics, from genetic testing to rare disorders; submitted by Debra Regier, M.D.
  • An app that would allow the Children’s National Childhood and Adolescent Diabetes Program team to communicate securely and efficiently with diabetes patients; submitted by Cynthia Medford, R.N., and Kannan Kasturi, M.D.
  • An app that would provide specific evidence-based guidance for medical providers considering PrEP (pre-exposure prophylaxis) for HIV prevention; submitted by Kyzwana Caves, M.D.

Kevin Cleary, Ph.D., technical director of the Bioengineering Initiative at Children’s National Health System, and Sean Cleary, Ph.D., M.P.H., associate professor in epidemiology and biostatistics at GW, created the hackathon to provide an interactive learning experience for people interested in developing medical and health software applications.

The workshop, which will be held on April 13, 2018, will start with short talks from experts on human factors engineering and the regulatory environment for medical and health apps. Attendees will then divide into small groups to brainstorm requirements and user interfaces for the 10 app ideas. After each group presents their concepts to all the participants, the judges will pick the winning app/group. The idea originator will receive up to $10,000 of voucher funding for their prototype development.

Neonatal baby

Multidisciplinary experts help CDC’s Zika research

“We are very excited about this next phase in our Zika research,” says Roberta L. DeBiasi, M.D., M.S. “It is a natural extension of our earlier participation as subject matter experts assisting as the CDC developed and published guidelines to inform the care of Zika-exposed and Zika-infected infants across the nation and U.S. territories.”

The Centers for Disease Control and Prevention (CDC) is funding three multidisciplinary experts from the Congenital Zika Virus Program at Children’s National Health System to collaborate on two of the CDC’s longitudinal Zika research projects in Colombia, South America.

“Zika en embarazadas y niños en Colombia” (ZEN) is a research study jointly designed by Colombia’s Instituto Nacional de Salud (INS) and the CDC to evaluate the association between Zika virus infection and adverse maternal, fetal and infant health outcomes. The study is following a large cohort of Colombian women from the first trimester of pregnancy, their male partners and their infants.

Under the six-month contract, Roberta L. DeBiasi, M.D., M.S., Sarah B. Mulkey, M.D., Ph.D., and Cara Biddle, M.D., M.P.H., will serve as consultants for the ZEN study providing expertise in pediatric infectious diseases, neurology, neurodevelopment and coordination of the complex care needs of Zika-affected infants.

The federal funding will underwrite the consultants’ work effort, as well as travel to the CDC’s headquarters in Atlanta and to research sites in Colombia. To that end, Drs. DeBiasi, Mulkey and Biddle participated in a December 2017 kickoff meeting, joining ZEN team leaders based in the U.S. at the CDC, as well as the INS in Colombia, with whom they will conduct research and collaborate academically.

Cara-Biddle-and-Sarah-Mulkey

Cara Biddle, M.D., M.P.H., and Sarah B. Mulkey, M.D., Ph.D., also will serve as consultants for the ZEN study.

“We are very excited about this next phase in our Zika research,” says Dr. DeBiasi, chief of the Division of Pediatric Infectious Diseases and co-director of the Children’s Zika program. “It is a natural extension of our earlier participation as subject matter experts assisting as the CDC developed and published guidelines to inform the care of Zika-exposed and Zika-infected infants across the nation and U.S. territories.”

Children’s National is leading its own longitudinal studies in Colombia that explore such questions as whether Zika-exposed infants whose neuroimaging appears normal when they are born experience any longer-term neurological issues and the role of genetics in neurologic injury following congenital Zika virus exposure and infection.

Human Rhinovirus

Finding the root cause of bronchiolitis symptoms

Human Rhinovirus

A new study shows that steroids might work for rhinovirus but not for respiratory syncytial virus.

Every winter, doctors’ offices and hospital emergency rooms fill with children who have bronchiolitis, an inflammation of the small airways in the lung. It’s responsible for about 130,000 admissions each year. Sometimes these young patients have symptoms reminiscent of a bad cold with a fever, cough and runny nose. Other times, bronchiolitis causes breathing troubles so severe that these children end up in the intensive care unit.

“The reality is that we don’t have anything to treat these patients aside from supportive care, such as intravenous fluids or respiratory support,” says Robert J. Freishtat, M.D., M.P.H., chief of emergency medicine at Children’s National Health System. “That’s really unacceptable because some kids get very, very sick.”

Several years ago, Dr. Freishtat says a clinical trial tested using steroids as a potential treatment for bronchiolitis. The thinking was that these drugs might reduce the inflammation that’s a hallmark of this condition. However, he says, the results weren’t a slam-dunk for steroids: The drugs didn’t seem to improve outcomes any better than a placebo.

But the trial had a critical flaw, he explains. Rather than having one homogenous cause, bronchiolitis is an umbrella term for a set of symptoms that can be caused by a number of different viruses. The most common ones are respiratory syncytial virus (RSV) and rhinovirus, the latter itself being an assortment of more than 100 different but related viruses. By treating bronchiolitis as a single disease, Dr. Freishtat says researchers might be ignoring the subtleties of each virus that influence whether a particular medication is useful.

“By treating all bronchiolitis patients with a single agent, we could be comparing apples with oranges,” he says. “The treatment may be completely different depending on the underlying cause.”

To test this idea, Dr. Freishtat and colleagues examined nasal secretions from 32 infants who had been hospitalized with bronchiolitis from 2011 to 2014 at 17 medical centers across the country that participate in a consortium called the 35th Multicenter Airway Research Collaboration. In half of these patients, lab tests confirmed that their bronchiolitis was caused by RSV; in the other half, the cause was rhinovirus.

From these nasal secretions, the researchers extracted nucleic acids called microRNAs. These molecules regulate the effects of different genes through a variety of different mechanisms, usually resulting in the effects of target genes being silenced. A single microRNA typically targets multiple genes by affecting messenger RNA, a molecule that’s key for producing proteins.

Comparing results between patients with RSV or rhinovirus, the researchers found 386 microRNAs that differed in concentration. Using bioinformatic software, they traced these microRNAs to thousands of messenger RNAs, looking for any interesting clues to important mechanisms of illness that might vary between the two viruses.

Their findings eventually turned up important differences between the two viruses in the NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway, a protein cascade that’s intimately involved in the inflammatory response and is a target for many types of steroids. Rhinovirus appears to upregulate the expression of many members of this protein family, driving cells to make more of them, and downregulate inhibitors of this cascade. On the other hand, RSV didn’t seem to have much of an effect on this critical pathway.

To see if these effects translated into cells making more inflammatory molecules in this pathway, the researchers searched for various members of this protein cascade in the nasal secretions. They found an increase in two, known as RelA and NFkB2.

Based on these findings, published online Jan. 17, 2018, in Pediatric Research, steroids might work for rhinovirus but not for RSV, notes Dr. Freishtat the study’s senior author.

“We’re pretty close to saying that you’d need to conduct a clinical trial with respect to the virus, rather than the symptoms, to measure any effect from a given drug,” he says.

Future clinical trials might test the arsenal of currently available medicines to see if any has an effect on bronchiolitis caused by either of these two viruses. Further research into the mechanisms of each type of illness also might turn up new targets that researchers could develop new medicines to hit.

“Instead of determining the disease based on symptoms,” he says, “we can eventually treat the root cause.”

Study co-authors include Kohei Hasegawa, study lead author, and Carlos A. Camargo Jr., Massachusetts General Hospital; Marcos Pérez-Losada, The George Washington University School of Medicine and Health Sciences; Claire E. Hoptay, Samuel Epstein and Stephen J. Teach, M.D., M.P.H., Children’s National; Jonathan M. Mansbach, Boston Children’s Hospital; and Pedro A. Piedra, Baylor College of Medicine.

drawing of neurons

Children’s National to host 28th Annual Pediatric Neurology Update

drawing of neurons

The Children’s National Health System Center for Neuroscience and Behavioral Medicine is proud to host the 28th Annual Pediatric Neurology Update course.

This year’s course will be focused on new understandings, molecular pathogenesis, novel treatment and outcomes of infections which affect the central nervous system; as well as the often indistinct boundaries between CNS infections and neuro immunologic diseases of the nervous system.

We invite you to join us for presentations from renowned experts in the field in this full-day, CME accredited event on May 3, 2018 at the Children’s National main campus in Washington, D.C.

For more information and to register, visit ChildrensNational.org/NeurologyUpdate.

Human Rhinovirus

When a common cold may trigger early supportive care

Human Rhinovirus

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

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

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

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

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

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

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

Geovanny Perez

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

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

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

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

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

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

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

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

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