Infectious Disease

physician looking at little girl's ear

Residents: Frontline defenders against antibiotic resistance?

physician looking at little girl's ear

A recent survey assessed whether residents knew which antibiotics were most appropriate for treating five common pediatric infections, including acute otitis media (ear infection).


Antibiotic resistance continues to grow around the world, with sometimes disastrous results. Some strains of bacteria no longer respond to any currently available antibiotic, making death by infections that were once easily treatable a renewed reality.

Avoiding this fate is possible, research suggests, if antibiotic prescribers do five essential things correctly: Give the right patient the right medication at the right dose through the right route at the right time. Medical residents – doctors who have finished medical school but are still receiving training at clinics and hospitals by working under more experienced physicians – are key to this strategy since they often are part of the frontline care team that selects and initiates antibiotic therapies. However, it has been unclear whether their prescribing patterns match these five “rights,” says Geovanny F. Perez, M.D., a pulmonologist at Children’s National Health System.

“Residents often decide which antibiotics to start a patient on, so they could become the first line of defense against antibiotic resistance,” Dr. Perez says. “They also could be an important target for education efforts if their prescribing patterns aren’t aligned with current guidelines.”

To determine whether residents are prescribing in ways that best avoid antibiotic resistance, Dr. Perez and colleagues sent an email survey to all 189 residents at two large children’s hospitals: Children’s National, a tertiary care center that serves patients throughout the greater Metropolitan Washington area at its main campus and network of primary care clinics; and Nicklaus Children’s Hospital, the largest freestanding pediatric hospital in South Florida.

The survey was divided into two parts. The first aimed to assess the knowledge of these residents about which antibiotics are most appropriate to treat five common pediatric infections: Acute otitis media (ear infection), group A streptococcal pharyngitis (strep throat), sinusitis (sinus infection), pneumonia and urinary tract infections.

The second part of the survey was meant to ascertain how residents acquired their antibiotic knowledge and prescribing behaviors. It asked about their awareness of antibiograms – a profile of which medications are effective against different local bacterial strains that is updated periodically at most hospitals – whether residents ever prescribed antibiotics for viral infections and the major influences on their prescribing decisions.

About one-half of the residents returned their surveys. Their answers suggested that most of them followed prescribing guidelines for the recommended drugs to treat otitis media, streptococcal pharyngitis and urinary tract infections. However, there were significant variations from guidelines for treating sinusitis and pneumonia, with many residents choosing antibiotics that were against current recommendations.

Additionally, only 3 percent of respondents indicated that they frequently used antibiograms, an important tool in selecting the most effective antibiotics. About one-half indicated that they sometimes used antibiograms, and one-quarter said that they never used an antibiogram. An additional 17 percent disclosed that they did not know what an antibiogram was. Even among those that knew about this important resource, about one-half said that they didn’t know where to access antibiograms specific to their hospitals.

Three-quarters of respondents indicated that they had prescribed antibiotics to patients who they considered to have a viral infection, rather than a bacterial one – a scenario in which antibiotics have no effect. In a follow-up question assessing the reasons for these decisions, 63 percent answered that they were following instructions from an attending physician or senior resident. More experienced physicians also played a more general role in shaping residents’ antibiotic knowledge: About 54 percent of residents said that their general pediatric inpatient attending physician – who oversees their training efforts – was their most influential source of knowledge in this area.

The findings, published in the September 2017 issue of Hospital Pediatrics, provide eye-opening insights into how residents prescribe antibiotics and their motivations for these choices, says Dr. Perez – particularly how the training they receive from mentors steers decisions many residents must make multiple times a day. He adds that antibiotic stewardship programs, which provide instruction to health care providers about current prescribing guidelines and practices, should focus on both residents and their resident charges for maximum impact.

“Ideally, we should be matching the guidelines 100 percent or at least close to it,” Dr. Perez says. “We think this goal is definitely attainable with the right training for both residents and their mentors alike.”

White children more likely to receive unnecessary antibiotics in ED

Although antibiotics can turn the tide for a variety of illnesses, they are ineffective against those caused by viruses. Despite this well-known fact, doctors often prescribe antibiotics for viral illnesses.

Infections now considered relatively easy to treat, including some forms of diarrhea and pneumonia, were the leading cause of death throughout the developed world until the 20th century. Then, scientists developed what eventually turned into a miracle cure: Antibiotics that could kill or thwart the growth of a broad array of bacterial species.

Although antibiotics can turn the tide for a variety of illnesses, they are ineffective against those caused by viruses. Despite this well-known fact, doctors often prescribe antibiotics for viral illnesses. Taking these drugs unnecessarily can fuel antibiotic resistance, giving rise to bacteria that don’t respond to the drugs that kept them in check in the past.

A new multicenter study shows how prevalent this scenario can be in hospitals’ Emergency Departments. This research, led by Monika K. Goyal, M.D., M.S.C.E., director of research in the Division of Emergency Medicine at Children’s National Health System, shows that non-Latino white children seeking treatment for viral infections in the Emergency Department (ED) are about twice as likely to receive an antibiotic unnecessarily compared with non-Latino black children or Latino children.

These findings, published online Sept. 5, 2017 in Pediatrics, echo similar racial and ethnic differences in treating acute respiratory tract infections in the primary care setting.

“It is encouraging that just 2.6 percent of children treated in pediatric EDs across the nation received antibiotics for viral acute respiratory tract infections since antibiotics are ineffective in treating viral infections,” Dr. Goyal says. “However, it is troubling to see such persistent racial and ethnic differences in how medications are prescribed, in this case in the ED. In addition to providing the best evidence-based care, we also strive to provide equitable care to all patients.”

Acute respiratory tract infections are among the most common reasons children are rushed to the ED for treatment, Dr. Goyal and co-authors write. Overprescribing antibiotics is also rampant for this viral ailment, with antibiotics erroneously prescribed for 13 percent to 75 percent of pediatric patients.

In the retrospective cohort study, the research team pored over deidentified electronic health data for the 2013 calendar year from seven geographically diverse pediatric EDs, capturing 39,445 encounters for these infections that met the study’s inclusion criteria. The patients’ mean age was 3.3 years old. Some 4.3 percent of non-Latino white patients received oral, intravenous or intramuscular antibiotics in the ED or upon discharge, compared with 2.6 percent of Latino patients and 1.9 percent of non-Latino black patients.

“A number of studies have demonstrated disparities with regards to how children of different ethnicities and races are treated in our nation’s pediatric EDs, including frequency of computed tomography scans for minor head trauma, laboratory and radiology tests and pain management. Unfortunately, today’s results provide further evidence of racial and ethnic differences in providing health care in the ED setting,” Dr. Goyal says. “Although, in this case, minority children received evidence-based care, more study is needed to explain why differences in care exist at all.”

At a time of growing antibiotic resistance, the study authors underscored the imperative to decrease excess antibiotic use in kids. Since the 1940s, the nation has relied on antibiotics to contend with diseases such as strep throat. Yet, according to the Centers for Disease Control and Prevention, at least 2 million people in the United States are infected with antibiotic-resistant bacteria each year.

According to the study authors, future research should explore the reasons that underlie racial and ethnic differences in antibiotic prescribing, including ED clinicians eager to appease anxious parents as well as implicit clinical bias. Dr. Goyal recently received a National Institutes of Health grant to further study racial and ethnic differences in how children seeking treatment at hospital EDs are managed.

“It may come down to factors as simple as providers or parents believing that ‘more is better,’ despite the clear public health risks of prescribing children antibiotics unnecessarily,” Dr. Goyal adds. “In this case, an intervention that educates parents and providers about appropriate antibiotic use could help the pediatric patients we care for today as well as in the future.”

Exchanging ideas

Exchanging ideas, best practices in China

Exchanging ideas

Physicians from the Children’s National delegation attended the Shanghai Pediatric Innovation Forum in June 2017. Pictured (left to right): Roberta DeBiasi, M.D., Michael Mintz, M.D., Robert Keating, M.D., Lawrence Jung, M.D., Peter Kim, M.D., and Sarah Birch, D.N.P., A.P.R.N.

In late June, a delegation of international pediatric experts from Children’s National Health System journeyed across the world to learn about the practice of pediatric medicine in China and to exchange ideas with colleagues there. Leaders from several of Children’s key specialties joined the delegation, including:

The group, led by Drs. Keating and Gaillard, traveled to China with Children’s Outreach Coordinator John Walsh, whose longtime connections and close familiarity with the pediatric medical community in Hangzhou and Shanghai made the collaboration possible. The team toured several of the largest children’s hospitals in country, including The Children’s Hospital of Zhejiang University School of Medicine in Hangzhou and Shanghai Children’s Medical Center, connecting with pediatric specialists there.

“Some of the most important parts of this trip were the opportunities to exchange ideas and solidify long term relationships that will allow us to work closely with our peers in China as they develop their pediatric programs. The potential is tremendous for unique collaborations between our teams and theirs for research and the development of clinical care improvements for children,” said Roger Packer, M.D., senior vice president of the Center for Neuroscience and Behavioral Health, who joined the delegation in Beijing.

A keynote lecture and more at the 3rd China International Forum on Pediatric Development

The delegation also was honored with an invitation to participate in the 3rd China International Forum on Pediatric Development. The forum is one of the largest pediatric focused meetings in the country and is led by all the major children’s hospitals in China, including those in Beijing and Shanghai. Close to 4,000 pediatricians attended the meeting, and presenters included esteemed international leaders in pediatric medicine from around the world.

Dr. Packer delivered one of the opening keynote lectures, entitled, “Translation of molecular advances into care: the challenge ahead for children’s hospitals.” His talk focused on the tremendous promise and significant challenges posed by the latest scientific advances, through the lens of a neurologist.

“Across the world, we are looking at the same challenges: How can we use scientific advances to find better outcomes? How can we financially support the new types of interventions made possible by these molecular biologics insights when they can cost millions of dollars for one patient?”

“There’s palpable excitement that these new developments will give us potential therapies we never dreamed about before, ways to reverse what we initially thought was irreversible brain damage, ways to prevent severe illnesses including brain tumors, but the issue is how to turn this promise into reality. That’s a worldwide issue, not simply a single country’s issue,” he continued.

He also flagged mental health and behavioral health as a crucial, universal challenge in need of addressing on both sides of the Pacific.

The Children’s National delegation, including Drs. DeBiasi, Song, Keating, Gaillard and Packer were also honored to share their insight in a series of specialty-specific breakout sessions at the Forum.

Overall, the long journey opened a dialogue between Children’s National and pediatric care providers in China, paving the way for future discussion about how to learn from each other and collaborate to enhance all institutions involved.

Roberta DeBiasi

Panel: Significant Zika risks linger for pregnant women and developing fetuses in US

Roberta DeBiasi

The threat from Zika “is not over. It is just beginning for the families who are affected by this,” says Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases and co-director of the Congenital Zika Virus Program at Children’s National Health System.

The Zika virus epidemic may have fallen off the radar for many media outlets, but significant risks continue to linger for pregnant women and developing fetuses, a panel of experts told staff working for U.S. Congressional leaders.

“The threat of this virus is real, and the threat continues,” Margaret Honein, Ph.D., M.P.H., of the Centers for Disease Control and Prevention’s (CDC) pregnancy and birth defects task force, said during the July 13 briefing held in the Russell Senate Office Building.

Dr. Honein told about 100 attendees that more than 200 Zika-affected babies have been born in the United States suffering from serious birth defects, such as rigid joints, inconsolable distress that causes them to cry continuously and difficulties swallowing. Some of these infants experience seizures that cause further brain damage.

Predicting what Zika will do next in the United States is very difficult, Dr. Honein said, adding that local outbreaks could occur “at any time.” A map she displayed showed Zika’s impact in shades of blue, with Zika infections documented in nearly every state and the highest number of infections – and deepest shade of blue­ – for California, Florida and Texas.

The threat from Zika “is not over. It is just beginning for the families who are affected by this,” agreed Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases and co-director of the Congenital Zika Virus Program at Children’s National Health System.

Since Children’s National launched its Zika program in May 2016, the multidisciplinary team has consulted on 65 mother-fetus/infant pairs, Dr. DeBiasi said. Because in utero Zika infection can result in a wide range of side effects, the Children’s team includes pediatric infectious diseases experts, fetal/neonatal neurologists to consult on seizures, audiologists to assess hearing, physical therapists and orthopaedists to contend with limb contractures, pulmonologists to relieve breathing problems and ophthalmologists to diagnose and treat vision disorders – among other specialists.

“You really need a program that has all of these areas of expertise available for a family,” Dr. DeBiasi told attendees. “It is not possible for a family to organize 27 different appointments if you have a child with these needs.”

Children’s Zika experts also collaborate with researchers in Colombia to gauge the ability of magnetic resonance imaging to produce earlier Zika diagnoses, to assess the role of viral load as biomarkers and to document Zika’s long-term impact on children’s neurodevelopment. The Colombia study has enrolled an additional 85 women/infant pairs.

In one presentation slide, Dr. DeBiasi showed sharp magnetic resonance imaging scans from their research study of a fetal brain at 18 and 22 weeks gestation that indicated clear abnormalities, including abnormal cortical folding. Ultrasound images taken at the exact same time points did not detect these abnormalities, she said.

Asked for advice by an attendee whose clinic treats women who regularly travel between California and Mexico, Dr. DeBiasi underscored the fact that Zika infection poses a risk to developing fetuses even if the pregnant woman has no symptoms of infection. “Whether or not they’re symptomatic, the risk is the same. It’s hard for people to understand that. That is No. 1,” she said.

Another challenge is for women who scrupulously follow the CDC’s guidance on lowering their infection risk while traveling. Upon return, those women may be unaware that they could still be exposed to Zika through unprotected sex with their partner who also has travelled, for as long as six months after travel.

Deer Tick

Treating Lyme disease: When do symptoms resolve in children?

Deer Tick

Some experts are predicting a rise in the number of ticks this year. That potential boom could lead to another boom – in Lyme disease, a bacterial illness transmitted specifically by deer ticks.

For many Americans, the warmer weather of summer means more time spent outside: More gardening and yard work, more hikes in the woods, more backyard barbecues. But for this year in particular, some experts predict warmer weather will lead to more ticks.

That potential boom in ticks could lead to another boom – in Lyme disease, a bacterial illness transmitted specifically by deer ticks. When ticks attach for at least 36 hours – what studies have shown is typically the lower bound needed to transmit Lyme-causing bacteria—many patients develop a bullseye-like rash at the site of the bite within seven to 10 days. If they’re not treated quickly, within weeks patients can develop symptoms such as headaches, heart arrhythmias, rashes and facial paralysis. Within months, Lyme can lead to arthritis, most commonly of the knee.

The standard treatment for Lyme disease is a course of antibiotics, such as oral doxycycline if the patient is older than 8 years old or amoxicillin if the child is younger than 8 – typically two weeks for early symptoms and longer for late symptoms. While the data showing when symptoms clear has been well established for adults, says Mattia Chason, M.D., a third-year resident at Children’s National Health System, little was known about how quickly symptoms typically resolve in children. That paucity of data can leave physicians and their families unsure about whether a child might need a repeat dose of antibiotics – or a different kind—or whether lingering symptoms might have a different cause.

To answer this question, he and colleagues – including Dr. Chason’s mentor, Roberta L. DeBiasi, M.D., M.S., chief of Children’s Division of Pediatric Infectious Diseases – looked at data in the electronic medical records of 79 children who were admitted to Children’s main hospital with a laboratory-confirmed diagnosis of Lyme disease from June 2008 to May 2015. The research team was particularly interested in children who had a headache – a strong marker of the early disseminated form of the disease – or pain and swelling of the knee, a strong marker of the late form of the disease.

Mattia Chason

Mattia Chason, M.D., and colleagues in infectious disease examined how quickly Lyme disease symptoms typically resolve in children, a research question that has received little prior study.

They found that after children with the early form of Lyme disease started treatment, their Lyme-associated headaches resolved rapidly – most within one to three days­ – no matter how long headaches were present before they came to the hospital for treatment.

However, for those with knee pain and swelling, the majority took between two to four weeks to resolve. The longer symptoms had been in place before treatment started, Dr. Chason says, the longer they tended to take to disappear.

The team also looked at a phenomenon called post-treatment Lyme disease syndrome, characterized by a constellation of symptoms, such as fatigue, generalized musculoskeletal pain and cognitive slowing, that can occur six months after an initial diagnosis of Lyme. Only two children out of the 79 met the criteria for this diagnosis, suggesting that it’s exceedingly rare in the pediatric population.

Taken as a whole, Dr. Chason says the findings provide a guide to doctors and family members alike on when to expect relief from Lyme symptoms. “Patients who come in with early symptoms tend to resolve rather quickly,” he says. “But for those with later symptoms, resolution can take quite some time. Those patients should see their doctors if there’s any suspicion of Lyme to get treatment sooner rather than later.”

Children’s infectious disease experts routinely advise parents about how to protect their children from Lyme disease. Their tips:

  • Help kids avoid exposure by either wearing long sleeves and pants – a tough sell in warm weather – or using repellents with 20 percent to 30 percent DEET. These repellents can be used on babies as young as 2 months old, Dr. Chason says, and are safe for most individuals.
  • Check for ticks anytime a child has spent time outside. The best way to perform them, Dr. Chason says, is to check the child each night. Before bath or bedtime, remove the child’s clothes and check every part of his or her body, including their hair, armpits, buttock region and the creases of the knee.
  • Remove ticks gently with tweezers to try to get as much of the arachnid out as possible.
  • Know what deer ticks look like. If you are unsure how to identify this species, save the tick or take a photo for your pediatrician to view.
  • If a tick has been attached for at least 36 hours, consult your child’s pediatrician for advice on whether the child will need prophylactic antibiotics.
zika virus

Will the Zika epidemic re-emerge in 2017?

Anthony Fauci

Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, discussed the possibility of a reemergence of Zika virus at Children’s National Research and Education Week.

Temperatures are rising, swelling the population of Aedes mosquitoes that transmit the Zika virus and prompting an anxious question: Will the Zika epidemic re-emerge in 2017?

Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIH), sketched out contrasting scenarios. Last year in Puerto Rico, at least 13 percent of residents were infected with Zika, “a huge percentage of the population to get infected in any one outbreak,” Dr. Fauci says. But he quickly adds: “That means that 87 percent of the population” did not get infected. When the chikungunya virus swept through the Caribbean during an earlier outbreak, it did so in multiple waves. “We are bracing for a return of Zika, but we shall see what happens.” Dr. Fauci says.

When it comes to the continental United States, however, previous dengue and chikungunya outbreaks were limited to southern Florida and Texas towns straddling the Mexican border. Domestic Zika transmission last year behaved in much the same fashion.

“Do we think we’re going to get an outbreak [of Zika] that is disseminated throughout the country? The answer is no,” Dr. Fauci adds. “We’re not going to see a major Puerto Rico-type outbreak in the continental United States.”

Dr. Fauci’s remarks were delivered April 24 to a standing-room-only auditorium as part of Research and Education Week, an annual celebration of the cutting-edge research and innovation happening every day at Children’s National. He offered a sweeping, fact-filled summary of Zika’s march across the globe: The virus was first isolated from a primate placed in a treehouse within Uganda’s Zika forest to intentionally become infected; Zika lurked under the radar for the first few decades, causing non-descript febrile illness; it bounced from country to country, causing isolated outbreaks; then, it transformed into an infectious disease of international concern when congenital Zika infection was linked to severe neural consequences for babies born in Brazil.

zika virus

Zika virus lurked under the radar for several decades, causing non-descript febrile illness; it bounced from country to country, resulting in isolated outbreaks; then, it transformed into an infectious disease of international concern.

“I refer to Brazil and Zika as the perfect storm,” Dr. Fauci told attendees. “You have a country that is a large country with a lot of people, some pockets of poverty and economic depression –  such as in the northeastern states –  without good health care there, plenty of Aedes aegypti mosquitoes and, importantly, a totally immunologically naive population. They had never seen Zika before. The right mosquitoes. The right climate. The right people. The right immunological status. And then, you have the explosion in Brazil.”

In Brazil, 139 to 175 babies were born each year with microcephaly – a condition characterized by a smaller than normal skull – from 2010 to 2014. From 2015 through 2016, that sobering statistic soared to 5,549 microcephaly cases, 2,366 of them lab-confirmed as caused by Zika.

Microcephaly “was the showstopper that changed everything,” says Dr. Fauci. “All of a sudden, [Zika] went from a relatively trivial disease to a disease that had dire consequences if a mother was infected, particularly during the first trimester.”

As Zika infections soared, ultimately affecting more than 60 countries, the virus surprised researchers and clinicians a number of times, by:

  • Being spread via sex
  • Being transmitted via blood transfusion, a finding from Brazil that prompted the Food and Drug Administration to recommend testing for all U.S. donated blood and blood products
  • Decimating developing babies’ neural stem cells and causing a constellation of congenital abnormalities, including vision problems and contractions to surviving infants’ arms and legs
  • Causing Guillain-Barré syndrome
  • Triggering transient hearing loss
  • Causing myocarditis, heart failure and arrhythmias

When it comes to the U.S. national response, Dr. Fauci says one of the most crucial variables is how quickly a vaccine becomes available to respond to the emerging outbreak. For Zika, the research community was able to sequence the virus and launch a Phase I trial in about three months, “the quickest time frame from identification to trial in the history of all vaccinology,” he adds.

Zika is a single-stranded, enveloped RNA virus that is closely related to dengue, West Nile, Japanese encephalitis and Yellow fever viruses, which gives the NIH and others racing to produce a Zika vaccine a leg up. The Yellow fever vaccine, at 99 percent effectiveness, is one of the world’s most effective vaccines.

“I think we will wind up with an effective vaccine. I don’t want to be over confident,” Dr. Fauci  says. “The reason I say I believe that we will is because [Zika is] a flavivirus, and we have been able to develop effective flavivirus vaccines. Remember, Yellow fever is not too different from Zika.”

Sarah Mulkey Columbia Zika Study

Damage may lurk in “normal” Zika-exposed brains

Sarah Mulkey Columbia Zika Study

An international study that includes Sarah B. Mulkey, M.D., Ph.D., aims to answer one of the most vexing questions about Zika: If babies’ brains appear “normal” at birth, have they survived Zika exposure in the womb with few neurological repercussions? Dr. Mulkey presented preliminary findings at PAS2017.

It has been well established by researchers, including scientists at Children’s National Health System, that the Zika virus is responsible for a slew of birth defects – such as microcephaly, other brain malformations and retinal damage – in babies of infected mothers. But how the virus causes these often devastating effects, and who exactly is affected, has not been explained fully.

Also unknown is whether exposed babies that appear normal at birth are truly unaffected by the virus or have hidden problems that might surface later. The majority of babies born to Zika-infected mothers in the United States appear to have no evidence of Zika-caused birth defects, but that’s no guarantee that the virus has not caused lingering damage.

Recently, Sarah B. Mulkey, M.D., Ph.D., made a trip to Colombia, where Children’s National researchers are collaborating on a clinical study. There, she tested Zika-affected babies’ motor skills as they sat, stood and lay facing upward and downward. The international study aims to answer one of the most vexing questions about Zika: If babies’ brains appear “normal” at birth, have they survived Zika exposure in the womb with few neurological repercussions?

“We don’t know the long-term neurological consequences of having Zika if your brain looks normal,” says Dr. Mulkey, a fetal-neonatal neurologist who is a member of Children’s Congenital Zika Virus Program. “That is what’s so scary, the uncertainty about long-term outcomes.”

According to the Centers for Disease Control and Prevention (CDC), one in 10 pregnancies across the United States with laboratory-confirmed Zika virus infection results in birth defects in the fetus or infant. For the lion’s share of Zika-affected pregnancies, then, babies’ long-term prospects remain a mystery.

“This is a huge number of children to be impacted and the impact, as we understand, has the potential to be pretty significant,” Dr. Mulkey adds.

Dr. Mulkey, the lead author, presented the research group’s preliminary findings during the 2017 annual meeting of the Pediatric Academic Societies (PAS). The presentation was one of several that focused on the Zika virus. Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases at Children’s National, organized two invited symposia devoted to the topic of Zika: Clinical perspectives and knowledge gaps; and the science of Zika, including experimental models of disease and vaccines. Dr. DeBiasi’s presentation included an overview of the 68 Zika-exposed or infected women and infants seen thus far by Children’s multidisciplinary Congenital Zika Virus Program.

“As the world’s largest pediatric research meeting, PAS2017 is an ideal setting for panelists to provide comprehensive epidemiologic and clinical updates about the emergence of Congenital Zika Syndrome and to review the pathogenesis of infection as it relates to the fetal brain,” Dr. DeBiasi says. “With temperatures already rising to levels that support spread of the Aedes mosquito, it is imperative for pediatricians around the world to share the latest research findings to identify the most effective interventions.”

As one example, Dr. Mulkey’s research sought to evaluate the utility of using magnetic resonance imaging (MRI) to evaluate fetal brain abnormalities in 48 babies whose mothers had confirmed Zika infection during pregnancy. Forty-six of the women/infant pairs enrolled in the prospective study are Colombian, and two are Washington, D.C. women who were exposed during travel to a Zika hot zone.

The women were infected with Zika during all three trimesters and experienced symptoms at a mean gestational age of 8.4 weeks. The first fetal MRIs were performed as early as 18 weeks’ gestation. Depending upon the gestational age when they were enrolled in the study, the participants had at least one fetal MRI as well as serial ultrasounds. Thirty-six fetuses had a second fetal MRI at about 31.1 gestational weeks. An experienced pediatric neuroradiologist evaluated the images.

Among the 48 study participants, 45 had “normal” fetal MRIs.

Three fetuses exposed to Zika in the first or second trimester had abnormal fetal MRIs:

  • One had heterotopia and an early, abnormal fold on the surface of the brain, indications that neurons did not migrate to their anticipated destination during brain development. This pregnancy was terminated at 23.9 gestational weeks.
  • One had parietal encephalocele, a rare birth defect that results in a sac-like protrusion of the brain through an opening in the skull. According to the CDC, this defect affects one in 12,200 births, or 340 babies, per year. It is not known if this rare finding is related to Zika infection.
  • One had a thin corpus callosum, dysplastic brainstem, heterotopias, significant ventriculomegaly and generalized cerebral/cerebellar atrophy.

“Fetal brain MRI detected early structural brain changes in fetuses exposed to the Zika virus in the first and second trimester,” Dr. Mulkey says. “The vast majority of fetuses exposed to Zika in our study had normal fetal MRI, however. Our ongoing study, underwritten by the Thrasher Research Fund, will evaluate their long-term neurodevelopment.”

Adré J. du Plessis, MB.Ch.B., M.P.H., director of the Fetal Medicine Institute and senior author of the paper, notes that this group “is a very important cohort to follow as long as Dr. Mulkey’s funding permits. We know that microcephaly is among the more devastating side effects caused by Zika exposure in utero. Unanswered questions remain about Zika’s impact on hearing, vision and cognition for a larger group of infants. Definitive answers only will come with long-term follow-up.”

Many of the Colombian families live in Sabanalarga, a relatively rural, impoverished area with frequent rain, leaving pockets of fresh water puddles that the mosquito that spreads Zika prefers, Dr. Mulkey adds. Families rode buses for hours for access to fetal MRI technology, which is not common in Colombia.

“The mothers are worried about their babies. They want to know if their babies are doing OK,” she says.

Advances in T-cell immunotherapy at ISCT

Healthy Human T Cell

T-cell immunotherapy, which has the potential to deliver safer, more effective treatments for cancer and life-threatening infections, is considered one of the most promising cell therapies today. Each year, medical experts from around the world – including leaders in the field at Children’s National Health System – gather at the International Society for Cellular Therapy (ISCT) Conference to move the needle on cell therapy through several days of innovation, collaboration and presentations.

Dr. Catherine Bollard, Children’s National chief of allergy and immunology and current president of ISCT, kicked off the week with a presentation on how specific approaches and strategies have contributed to the success of T-cell immunotherapy, a ground-breaking therapy in this fast-moving field.

Later in the week, Dr. Kirsten Williams, a blood and marrow transplant specialist, presented encouraging new findings, demonstrating that T-cell therapy could be an effective treatment for leukemia and lymphoma patients who relapse after undergoing a bone marrow transplant. Results from her phase 1 study showed that four out of nine patients achieved complete remission. Other medical options for the patients involved – those who relapsed between 2 and 12 months post-transplant – are very limited. Looking to the future, this developing therapy, while still in early stages, could be a promising solution.

Other highlights include:

  • Both Allistair Abraham, blood and marrow transplantation specialist, and Dr. Michael Keller, immunologist, presented oral abstracts, the former titled “Successful Engraftment but High Viral Reactivation After Reduced Intensity Unrelated Umbilical Cord Blood Transplantation for Sickle Cell Disease” and the latter “Adoptive T Cell Immunotherapy Restores Targeted Antiviral Immunity in Immunodeficient Patients.
  • Patrick Hanley engaged attendees with his talk, “Challenges of Incorporating T-Cell Potency Assays in Early Phase Clinical Trials,” and his poster presentation “Cost Effectiveness of Manufacturing Antigen-Specific T-Cells in an Academic GMP Facility.” He also co-chaired a session titled “Early Stage Professionals Session 1 – Advanced Strategic Innovations for Cell and Gene Therapies.”
  • To round out this impressive group, Shabnum Piyush Patel gave a talk on genetically modifying HIV-specific T-cells to enhance their anti-viral capacity; the team plans to use these HIV-specific T-cells post-transplant in HIV-positive patients with hematologic malignancies to control their viral rebound.

This exciting team is leading the way in immunology and immunotherapy, as evidenced by the work they shared at the ISCT conference and their ongoing commitment to improving treatments and outcomes for patients at Children’s National and across the country. To learn more about the team, visit the Center for Cancer and Blood Disorders site.

Research and Education Week 2017 recap: The immunization battle

Boris D. Lushniak

Boris D. Lushniak, M.D., M.P.H., Dean of University of Maryland School of Public Health and former deputy surgeon general speaks at Research and Education Week 2017 at Children’s National.

Children’s National Health System recently held its 7th Annual Research and Education Week, inviting many keynote and special lecturers to share insights on the most recent research and education findings. Boris D. Lushniak, M.D., M.P.H., dean of the School of Public Health at the University of Maryland and former deputy surgeon general, was just one of many renowned keynote speakers to grace the stage.

In his presentation, “The immunization battle: Perspectives from a public health guy,” Dr. Lushniak described public health as the “science and art of preventing disease, prolonging health and preventing disease through the organized efforts and informed choices of all.” He discussed immunizations across the years, highlighting past achievements in the public health world, the current state of childhood immunizations, and how to improve the view and impact of immunizations and vaccinations in the future.

Since the 1900s, there have been great achievements in the public health world from vaccinations and child immunizations to the recognition of tobacco as a health hazard. Statistics have revealed how child immunizations are the most cost-effective clinical preventive service with a high return on investment. According to Healthy People 20/20, birth cohorts vaccinated according to the childhood immunization schedule provided by the Center for Disease Control saved 33,000 lives, prevented 14 million cases of disease, reduced direct health care costs by $9.9 billion and saved $33.4 billion in indirect health care costs.

Although the statistics have value to medical professionals, Dr. Lushniak explained how the personal views of patients and families create barriers for advancement. The March 2016 Journal of American Medical Association reported that 300 children in the United States die from vaccine-preventable diseases each year; each case representing a failed opportunity to prevent disease due to vaccine refusal and a decrease in community  immunity.

Based on the views of the Journal of Health Management & Practice¸ Dr. Lushniak recommends following these tips to increase vaccine rates:

  • Creating or supporting effective interventions (client reminder, recall systems, provider assessment/feedback/reminder)
  • Generating and evaluating public health response to outbreaks
  • Facilitating vaccine management and accountability
  • Determining client vaccination status or decisions made by clinicians, health departments, schools
  • Aiding surveillance and investigations on vaccination rates, missed opportunities, invalid doses and disparities in coverage

Dr. Lushniak concluded his presentation by encouraging the audience to keep working towards the advancement of immunization, despite any perceptions against getting children vaccinated.

Drs. DeBiasi and du Plessis

Zika virus, one year later

Drs. DeBiasi and du Plessis

A multidisciplinary team at Children’s National has consulted on 66 Zika-affected pregnancies and births since May 2016.

The first pregnant patient with worries about a possible Zika virus infection arrived at the Children’s National Health System Fetal Medicine Institute on Jan. 26, 2016, shortly after returning from international travel.

Sixteen months ago, the world was just beginning to learn how devastating the mosquito-borne illness could be to fetuses developing in utero. As the epidemic spread, a growing number of sun-splashed regions that harbor mosquitoes that efficiently spread the virus experienced a ballooning number of Zika-affected pregnancies and began to record sobering birth defects.

The Washington, D.C. patient’s concerns were well-founded. Exposure to Zika virus early in her pregnancy led to significant fetal brain abnormalities, and Zika virus lingered in the woman’s bloodstream months after the initial exposure — longer than the Centers for Disease Control and Prevention (CDC) then thought was possible.

The research paper describing the woman’s lengthy Zika infection, published by The New England Journal of Medicine, was selected as one of the most impactful research papers written by Children’s National authors in 2016.

In the intervening months, a multidisciplinary team at Children National has consulted on 66 pregnancies and infants with confirmed or suspected Zika exposure. Thirty-five of the Zika-related evaluations were prenatal, and 31 postnatal evaluations assessed the impact of in utero Zika exposure after the babies were born.

The continuum of Zika-related injuries includes tragedies, such as a 28-year-old pregnant woman who was referred to Children’s National after imaging hinted at microcephaly. Follow-up with sharper magnetic resonance imaging (MRI) identified severe diffuse thinning of the cerebral cortical mantle, evidence of parenchymal cysts in the white matter and multiple contractures of upper and lower extremities with muscular atrophy.

According to a registry of Zika-affected pregnancies maintained by the CDC, one in 10 pregnancies across the United States with laboratory-confirmed Zika virus infection has resulted in birth defects in the fetus or infant.

“More surprising than that percentage is the fact that just 25 percent of infants underwent neuroimaging after birth – despite the CDC’s recommendation that all Zika-exposed infants undergo postnatal imaging,” says Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases and co-director of the Congenital Zika Virus Program at Children’s National. “Clinicians should follow the CDC’s guidance to the letter, asking women about possible exposure to Zika and providing multidisciplinary care to babies after birth. Imaging is an essential tool to accurately monitor the growing baby’s brain development.”

Adré du Plessis, M.B.Ch.B., M.P.H., director of the Fetal Medicine Institute and Congenital Zika Virus Program co-leader, explains the challenges: ”When it comes to understanding the long-term consequences for fetuses exposed to the Zika virus, we are still on the steepest part of the learning curve. Identifying those children at risk for adverse outcomes will require a sustained and concerted multidisciplinary effort from conception well beyond childhood.”

In addition to counseling families in the greater Washington, D.C. region, the Children’s research team is collaborating with international colleagues to conduct a clinical trial that has been recruiting Zika-infected women and their babies in Colombia. Pediatric Resident Youssef A. Kousa, D.O., Ph.D., M.S., and Neurologist Sarah B. Mulkey, M.D., Ph.D., will present preliminary findings during Research and Education Week 2017.

In Colombia as well as the District of Columbia, a growing challenge continues to be assessing Zika’s more subtle effects on pregnancies, developing fetuses and infants, says Radiologist Dorothy Bulas, M.D., another member of Children’s multidisciplinary Congenital Zika Virus Program.

The most severe cases from Brazil were characterized by interrupted fetal brain development, smaller-than-normal infant head circumference, brain calcifications, enlarged ventricles, seizures and limbs folded at odd angles. In the United States and many other Zika-affected regions, Zika-affected cases with such severe birth defects are outnumbered by infants who were exposed to Zika in utero but have imaging that appears normal.

In a darkened room, Dr. Bulas pores over magnified images of the brains of Zika-infected babies, looking for subtle differences in structure that may portend future problems.

“There are some questions we have answered in the past year, but a number of questions remain unanswered,” Dr. Bulas says. “For neonates, that whole area needs assessment. As the fetal brain is developing, the Zika virus seems to affect the progenitor cells. They’re getting hit quite early on. While we may not detect brain damage during the prenatal period, it may appear in postnatal images. And mild side effects that may not be as obvious early on still have the potential to be devastating.”

test tubes

2016: A banner year for innovation

test tubes

In 2016, clinicians and research scientists working at Children’s National Health System published more than 1,100 articles in high-impact journals about a wide array of topics. A Children’s Research Institute review group selected the top articles for the calendar year considering, among other factors, work published in top-tier journals with impact factors of 9.5 and higher.

“Conducting world-class research and publishing the results in prestigious journals represents the pinnacle of many research scientists’ careers. I am pleased to see Children’s National staff continue this essential tradition,” says Mark L. Batshaw, M.D., Physician-in-Chief and Chief Academic Officer at Children’s National. “While it was difficult for us to winnow the field of worthy contenders to this select group, these papers not only inform the field broadly, they epitomize the multidisciplinary nature of our research,” Dr. Batshaw adds.

The published papers explain research that includes discoveries made at the genetic and cellular levels, clinical insights and a robotic innovation that promises to revolutionize surgery:

  • Outcomes from supervised autonomous procedures are superior to surgery performed by expert surgeons
  • The Zika virus can cause substantial fetal brain abnormalities in utero, without microcephaly or intracranial calcifications
  • Mortality among injured adolescents was lower among patients treated at pediatric trauma centers, compared with adolescents treated at other trauma center types
  • Hydroxycarbamide can substitute for chronic transfusions to maintain transcranial Doppler flow velocities for high-risk children with sickle cell anemia
  • There is convincing evidence of the efficacy of in vivo genome editing in an authentic animal model of a lethal human metabolic disease
  • Sirt1 is an essential regulator of oligodendrocyte progenitor cell proliferation and oligodendrocyte regeneration after neonatal brain injury

Read the complete list.

Dr. Batshaw’s announcement comes on the eve of Research and Education Week 2017 at Children’s National, a weeklong event that begins April 24. This year’s theme, “Collaboration Leads to Innovation,” underscores the cross-cutting nature of Children’s research that aims to transform pediatric care.

vaccination

How to talk with parents who are vaccine hesitant

vaccination

The single most important factor in parents deciding to accept vaccines is one-on-one contact with an informed, caring and concerned pediatrician.

When facing vaccine-hesitant parents, the key for me is to be collaborative and not to dismiss their questions or concerns.  That’s why the American Academy of Pediatrics advises pediatricians to talk with parents to determine their individual concerns so we can address them. The decision whether to immunize a child ultimately rests with the parents. It’s understandable for parents to be worried – but it also critical that they get the facts.

The conversation can begin simply.

Here’s what I say to vaccine-hesitant parents: You work hard to protect your child every day. Vaccines are as important as feeding your child healthy foods, using a car seat or seat belt and installing a smoke detector.

Here’s what I ask vaccine-hesitant parents: What information can I provide to help you make an informed decision, or to help you feel comfortable with vaccinating your child?  As with most of what we pediatricians do, my goal is to partner with the parent so that we help their child to attain optimal health as a team.

I am a parent. Although my husband and I did not hesitate in vaccinating our daughter, I understand why parents want to feel comfortable about the choices they make for their children.

I also am a pediatrician. I have seen children die from the flu or develop a life-threatening brain infection from chickenpox.  Thanks to the herd immunity that results from decades of vaccination, many of these diseases are now rare in the United States, but there are still episodic outbreaks throughout the country that remind us why we vaccinate children.

Vaccinating is the norm.  Only about 1 percent of children in the United States receive no vaccinations. Most parents who are hesitant about vaccines are not opposed to immunizing their children; they are unsure or have unanswered questions. Fortunately, most vaccine-hesitant parents are responsive to receiving information about vaccines, consider vaccinating their children and do not oppose all vaccines.

When it comes to vaccine-hesitant parents, one-on-one counseling is effective. The single most important factor in parents deciding to accept vaccines is one-on-one contact with an informed, caring and concerned pediatrician.

About the Author

Lanre Omojokun FalusiLanre Omojokun Falusi, M.D., F.A.A.P.
General pediatrician and Associate Medical Director for Municipal and Regional Affairs at Child Health Advocacy Institute

Sarah B. Mulkey

Researchers tackle Zika’s unanswered questions

Youssef A. Kousa

Youssef A. Kousa, D.O., Ph.D., M.S., is examining whether interplays between certain genes make some women more vulnerable to symptomatic Zika infections.

A Maryland woman traveled to the Dominican Republic early in her pregnancy, spending three weeks with family. She felt dizzy and tired and, at first, attributed the lethargy to jet lag. Then, she experienced a rash that lasted about four days. She never saw a bite or slapped a mosquito while in the Dominican Republic but, having heard about the Zika virus, asked to be tested.

Her blood tested positive for Zika.

Why was this pregnant woman infected by Zika while others who live year-round in Zika hot zones remain free of the infectious disease? And why was she among the slim minority of Zika-positive people to show symptoms?

Youssef A. Kousa, D.O., Ph.D., M.S., a pediatric resident in the child neurology track at Children’s National Health System, is working on a research study that will examine whether interplays between certain genes make some women more vulnerable to symptomatic Zika infections during pregnancy, leaving  some fetuses at higher risk of developing microcephaly.

Dr. Kousa will present preliminary findings during Research and Education Week 2017 at Children’s National.

At sites in Puerto Rico, Colombia and Washington D.C., Dr. Kousa and his research collaborators are actively recruiting study participants and drawing blood from women whose Zika infections were confirmed in the first or second trimester of pregnancy. The blood is stored in test tubes with purple caps, a visual cue that the tube contains an additive that binds DNA, preventing it from being cut up. Additional research sites are currently being developed.

When the blood arrives at Children’s National, Dr. Kousa will use a centrifuge located in a sample preparation room to spin the samples at high speed for 11 minutes. The sample emerges from the centrifuge in three discrete layers, separated by weight. The rose-colored section that rises to the top is plasma. Plasma contains tell-tale signs of the immune system’s past battles with viruses and will be analyzed by Roberta L. DeBiasi, M.D., M.S., Chief of the Division of Pediatric Infectious Diseases at Children’s National, and Dr. Kousa’s mentor.

A slender line at the middle indicates white blood cells. The dark red layer is heavier red blood cells that sink to the bottom. This bottom half of the test tube, where the DNA resides, is where Dr. Kousa will perform his genetic research.

For years, Dr. Kousa has worked to identify genetic risk factors that influence which fetuses develop cleft lip and palate. In addition to genetic variances that drive disease, he looks at environmental overlays that can trigger genes to respond in ways that cause pediatric disease. When Zika infections raced across the globe, he says it was important to apply the same genetic analyses to the emerging disease. Genes make proteins that carry out instructions, but viral infection disrupts how genes interact, he says. Cells die. Other cells do not fully mature.

While certain poverty-stricken regions of Brazil have recorded the highest spikes in rates of microcephaly, more is at play than socioeconomics, he says. “It didn’t feel like all of the answers lie in the neighborhood. One woman with a Zika-affected child can live just down the street from a child who is more or less severely affected by Zika.”

As a father, Dr. Kousa is particularly concerned about how Zika stunts growth of the fetal brain at a time when it should expand exponentially. “I have three kids. You see them as they achieve milestones over time. It makes you happy and proud as a parent,” he says.

Sarah B. Mulkey

Sarah B. Mulkey, M.D., Ph.D., is studying whether infants exposed to Zika in utero achieve the same developmental milestones as uninfected infants.

While Dr. Kousa concentrates on Zika’s most devastating side effects, his colleague Sarah B. Mulkey, M.D., Ph.D., is exploring more subtle damage Zika can cause to fetuses exposed in utero. In the cohort of Colombian patients that Dr. Mulkey is researching, just 8 percent had abnormal fetal brain magnetic resonance images (MRIs). At first glance, the uncomplicated MRIs appear to be reassuring news for the vast majority of pregnant women.

Dr. Mulkey also will present preliminary findings during Research and Education Week 2017 at Children’s National.

In the fetus, the Zika virus makes a beeline to the developing brain where it replicates with ease and can linger after birth. “We need to be cautious about saying the fetal MRI is ‘normal’ and the infant is going to be ‘normal,’ ” Dr. Mulkey says. “We know with congenital cytomegalovirus that infected infants may not show symptoms at birth yet suffer long-term consequences, such as hearing deficits and vision loss.”

Among Zika-affected pregnancies in Colombia in which late-gestational age fetal MRIs were normal, Dr. Mulkey will use two different evaluation tools at 6 months and 1 year of age to gauge whether the babies accomplish the same milestones as peers. One evaluation tool is a questionnaire that has been validated in Spanish.

At 6 months and 1 year of age, the infants’ motor skills will be assessed, such as their ability to roll over in both directions, sit up, draw their feet toward their waist, stand, take steps independently and purposefully move their hands. Videotapes of the infants performing the motor skills will be scored by Dr. Mulkey and her mentor, Adre du Plessis, M.B.Ch.B., Chief of the Division of Fetal and Transitional Medicine at Children’s National. The Thrasher Research Fund is funding the project, “Neurologic outcomes of apparently normal newborns from Zika virus-positive pregnancies,” as part of its Early Career Award Program.

Both research projects are extensions of a larger multinational study co-led by Drs. du Plessis and DeBiasi that explores the impact of prolonged Zika viremia in pregnant women, fetuses and infants; the feasibility of using fetal MRI to describe the continuum of neurological impacts in Zika-affected pregnancies; and long-term developmental issues experienced by Zika-affected infants.

Taking telemedicine to heart

For seven years, a Children’s National team has worked on new technologies to blunt the severity of rheumatic heart disease around the world, vastly improving patients’ chances of avoiding serious complications.

Rheumatic heart disease (RHD) is caused by repeated infections from the same bacteria that cause strep throat, which progressively lead to worsening inflammation of the heart’s valves with each successive infection. Over time, these valves thicken with scar tissue and prevent the heart from effectively pumping life-sustaining, oxygenated blood. The devastating condition, which was endemic in the United States before 1950, is now so rare that few outside the medical community have even heard of it. But in the developing world, explains Craig Sable, M.D., director of echocardiography and pediatric cardiology fellowship training and medical director of telemedicine at Children’s National Health System, RHD is nearly as common as HIV.

“RHD is the world’s forgotten disease,” Dr. Sable says. An estimated 32.9 million people worldwide have this condition, most of whom reside in low- to middle-income countries — places that often lack the resources to effectively diagnose and treat it.

Dr. Sable, Andrea Z. Beaton, M.D., and international colleagues plan to overturn this paradigm. For the last seven years, the team has worked on developing new technologies that could blunt the severity of RHD, vastly improving patients’ chances of avoiding its most serious complications.

At the heart of their approach is telemedicine — the use of telecommunications and information technology to provide clinical support for doctors and other care providers who often practice a substantial distance away. Telemedicine already has proven extremely useful within resource-rich countries, such as the United States, according to Dr. Sable. He and Children’s National colleagues have taken advantage of it for years to diagnose and treat pediatric disease from a distance, ranging from diabetes to asthma to autism. In the developing world, he says, it could be a game-changer, offering a chance to equalize healthcare between low- and high-resource settings.

In one ongoing project, a team led by Drs. Sable and Beaton is using telemedicine to screen children for RHD, a critical step to making sure that kids whose hearts already have been damaged receive the antibiotics and follow-up necessary to prevent further injury. After five years of working in Africa, the team recently expanded their project to Brazil, a country riddled with the poverty and overcrowding known to contribute to RHD.

Starting in 2014, the researchers began training four non-physicians, including medical technicians and nurses, to use handheld ultrasound machines to gather the precise series of heart images required for RHD diagnosis. They deployed these healthcare workers to schools in Minas Gerais, the second-most populous state in Brazil, to screen children between the ages of 7 and 18, the population most likely to be affected. With each worker scanning up to 30 children per day at 21 area schools, the researchers eventually amassed nearly 6,000 studies in 2014 and 2015.

Each night, the team on the ground transmitted their data to a cloud server, from which Children’s cardiologists, experts in RHD, and a regional hospital, Universidade Federal de Minas Gerais, accessed and interpreted the images.

“There was almost zero downtime,” Dr. Sable remembers. “The studies were transferred efficiently, they were read efficiently, and the cloud server allowed for easy sharing of information if there was concern about any questionable findings.”

In a study published online on November 4, 2016 in the Journal of Telemedicine and Telecare, Dr. Sable and colleagues reported the project’s success. Together, the team diagnosed latent heart disease in 251 children — about 4.2 percent of the subjects screened — allowing these patients to receive the regular antibiotics necessary to prevent further valve damage, and for those with hearts already badly injured to receive corrective surgery.

The researchers continued to collect data after the manuscript was submitted for publication. The team, which includes Drs. Bruno R. Nascimento, Adriana C. Diamantino, Antonio L.P. Ribeiro and Maria do Carmo P. Nunes, has screened a total of roughly 12,000 Brazilian schoolchildren to date.

Dr. Sable notes there is plenty of room for improvement in the model. For example, he says, the research team has not found a low-bandwidth solution to directly transmit the vast amount of data from each screening in real time, which has caused a slight slowdown of information to the hospital teams. The team eventually hopes to incorporate RHD screenings into annual health exams at local health clinics, sidestepping potential drawbacks of school day screenings.

Overall, being able to diagnose RHD using non-physicians and portable ultrasounds could eventually help Minas Gerais and additional low- to middle-income areas of the world where this disease remains endemic reach the same status as the United States and other resource-heavy countries.

“We’re putting ultrasound technology in the hands of people who otherwise wouldn’t have it,” says Dr. Sable, “and it could have a huge impact on their overall health.”

This work was supported by a grant from the Verizon Foundation and in-kind donations from General Electric and ViTelNet.

Thrasher Research Fund supports Zika virus neurologic outcomes study

The Thrasher Research Fund will fund a Children’s National project, “Neurologic Outcomes of Apparently Normal Newborns From Zika Virus-Positive Pregnancies,” as part of its Early Career Award Program, an initiative designed to support the successful training and mentoring of the next generation of pediatric researchers.

The project was submitted by Sarah B. Mulkey, M.D., Ph.D., a fetal-neonatal neurologist who is a member of the Congenital Zika Virus Program at Children’s National. During the award period, Dr. Mulkey will be mentored by Adre du Plessis, M.B.Ch.B., director of the Fetal Medicine Institute, and Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases. Drs. du Plessis and DeBiasi co-direct the multidisciplinary Zika program, one of the nation’s first.

In the award letter, the fund mentioned Children’s institutional support for Dr. Mulkey, as demonstrated by the mentors’ letter of support, as “an important consideration throughout the funding process.”

Doctors working together to find treatments for autoimmune encephalitis

Children’s and Regeneron partner in exome sequencing study

Children’s National, in partnership with the Regeneron Genetics Center (RGC, a subsidiary of Regeneron Pharmaceuticals, Inc.), has announced the launch of a major three-year research study that will examine the links between undiagnosed disease and an individual’s genetic profile.

The program, directed by Children’s National Geneticist Carlos Ferreira Lopez, M.D., and coordinated by Genetic Counselor Lindsay Kehoe, hopes to include as many as 3,000 patients in its initial year and even greater numbers in the following two years.

During the course of the study, RGC will conduct whole exome sequencing (WES) to examine the entire protein-coding DNA in a patient’s genome. Children’s National geneticists will analyze and screen for certain findings that are known to be potentially causative or diagnostic of disease. Children’s National scientists and providers will confirm preliminary research findings in a lab certified for Clinical Laboratory Improvement Amendments (CLIA), per federal standards for clinical testing, and refer any confirmatory CLIA-certified cases to appropriate clinicians at Children’s National for further care.

According to Marshall Summar, M.D., Chief of Genetics and Metabolism at Children’s National, the WES study could finally provide patients and their families with the medical answers they have been looking for, allowing for treatment appropriate to their specific genetic condition.

Because pediatric diseases can often elude diagnosis, they can pose a number of detrimental effects to patients and their families, including treatment delays, multiple time- and cost-intensive tests, and stress from lingering uncertainty regarding the illness. With this genomic data, Regeneron will be able to utilize findings to continue its efforts to improve drug development.

Since its inception in 2014, the RGC has strategically partnered with leading medical institutions to utilize human genetics data to speed the development and discovery of new and improved therapies for patients in need.

‘Trojan horse’ macrophage TNF-alpha opens door for HIV-1 to enter kidney epithelial cells, causing nephropathy

macrophage

Like a Trojan horse, the macrophage sits atop the epithelial cell with HIV hidden inside, opening a doorway into the kidney cell for high levels of HIV-1 to enter.

When nephrologist Patricio Ray, M.D., began investigating human immunodeficiency virus (HIV) as a renal fellow, children infected with the virus had a life expectancy of no more than seven years, and kids of African descent curiously were developing a type of HIV-related kidney disease.

HIV-associated nephropathy (HIVAN) is a progressive kidney disease seen in people who are both HIV-positive and of African ancestry. Kids who carry a modified protein that protects them against sleeping sickness are 80 times more likely to develop this type of kidney disease. Due to the kidney damage, they can have abnormal amounts of protein in their urine, focal segmental glomerulosclerosis, and microcystic tubular dilation, which can lead to enlarged kidneys and chronic kidney failure.

“No one understood how HIV could affect kidney cells that lack the receptors expressed in T cells and white cells,” recalls Dr. Ray, Robert Parrott Professor of Pediatrics at Children’s National Health System. Virologists said kidney epithelial cells that lacked CD4, a major receptor where HIV attaches, could not be infected with the virus. Nephrologists, meanwhile, were seeing that HIV infection was damaging these cells.

It’s taken two decades to unravel the medical mystery, aided by urine samples he coaxed kids to donate by offering them the latest music from New Kids on the Block in exchange for each urine bottle. Many of the kids died years ago, but their immortalized cells were essential in determining, through a process of elimination, which renal cell types were capable of being infected by HIV-1.

The paper represents the capstone of Dr. Ray’s career.

“This is how difficult it is to get an important contribution in science,” he says. “It’s 20 years of work involving the excellent contributions of many people, but that’s why research is called research. In the end, it’s all a learning process. But, it’s amazing how the puzzle pieces begin to fit. When the puzzle fits, it’s good.”

Dr. Ray, in collaboration with lead author Jinliang Li, Ph.D., and four additional Children’s National co-authors, published a paper November 3 in the Journal of the American Society of Nephrology that establishes a new role for transmembrane TNF-alpha, that of a facilitator that makes it easier for the HIV virus to enter certain cell types and replicate there.  Like a Trojan horse, the macrophage sits atop the epithelial cell with HIV hidden inside, opening a doorway into the kidney cell for high levels of HIV-1 to enter.

As a starting point, the research team cultured podocytes from the urine of kids with HIVAN. Through a number of steps, they isolated the unique contributions of the HIV envelope, heparan sulfate proteoglycans as attachment receptors – the glue that binds HIV to podocytes – and the essential role played by TNF-a, a 212-amino acid long type 2 transmembrane protein, in regulating at least two processes, including viral entry and fusion. They used a fluorescent marker to tag HIV-1 viruses, so it lit up bright green. Thus primed with transmembrane TNF-a, the podocytes were susceptible to HIV-1 infection when exposed to high viral loads.

Additional research is needed, such as in vitro work to help understand how HIV traffics within the cell, Dr. Ray says. Those insights could winnow the list of existing therapies that could block key steps, such as attachment to the viral envelope, which could help all people of African descent carrying the genetic mutation, including underserved kids in sub-Saharan Africa.

Another open research question is that certain cells located in the placenta and cervix express TNF-a, and may be more likely to be infected by HIV. Blocking that process could help prevent pregnant HIV-positive mothers from transmitting illness to their offspring.

Efficacy of family-centered advanced care planning for adolescents with HIV and their families

Led by experts at Children’s National Health System and the Adolescent Palliative Care Consortium, a new study published in Pediatrics reports that pediatric advanced care planning (pACP) can provide a positive environment for adolescents with Human Immunodeficiency Virus (HIV) and their families to discuss end of life care. Being born with HIV increases an adolescent’s risk of dying from an opportunistic infection or chronic illness, underscoring the need for pACP and the significance of this research.

Read more here.

Learning platform teaches clinicians how to spot and treat malaria

Children’s National experts are outlining a novel approach to helping healthcare providers learn how to diagnose and manage malaria; the online tool provides real-time feedback about their decision making.

Children’s National experts are outlining a novel approach to helping healthcare providers learn how to diagnose and manage malaria; the online tool provides real-time feedback about their decision making.

Next-generation medical education looks like this: A white-coat wearing avatar with the voice, face, and know-how of one of the nation’s leading infectious disease experts walks you through the twists and turns of how to diagnose malaria, making stops in a variety of hospital settings. If you make the right diagnostic and treatment decisions, you get instantaneous gold stars. If your choices are off-the-mark, at each decision point you get a clear explanation of why your answer was incorrect.

“This is the future of medical education,” says Barbara Jantausch, M.D., F.A.A.P., F.I.D.S.A., an infectious disease specialist at Children’s National Health System. She’s the female avatar with the John Travolta dance moves and expertise about malaria’s epidemiology, diagnosis, and treatment.

Dr. Jantausch will present a poster, “The Hot Zone: An Online Decision-Centered Vignette Player for Teaching Clinical Diagnostic Reasoning Skills,” during IDWeek 2016, the annual meeting of the Infectious Diseases Society of America. “It’s case-based, interactive e-learning where you choose your own adventure. The beauty of this module is the training can be self-directed,” Dr. Jantausch adds.

“At Children’s National, we’re pioneering the effort to build discovery-based learning platforms,” says Jeff Sestokas, Director of eLearning. In the vignette player, he’s the male avatar named Dr. Bear. Malaria is the first infectious disease training module but others are planned for the global health series, including Chagas disease and Zika virus, Sestokas says.

Identifying the illness

According to the Centers for Disease Control & Prevention (CDC), in 2015 an estimated 214 million people around the world had malaria, a mosquito-borne illness, and 438,000 of them died. Because of the lengthy incubation period, many international travelers do not show malaria symptoms until they return to the United States and experience flu-like symptoms including high fevers, shaking chills, and dehydration. Their lab results may include metabolic acidosis, hypoglycemia, normocytic anemia, or thrombocytopenia. At Children’s, 25 percent of children admitted with travel-related malaria are admitted to the intensive care unit.

“This started as a way to offer people in areas that do not see as many patients with malaria an opportunity to learn the same critical thinking skills,” she adds.

People who click through the vignettes play the role of a clinician working in the emergency department whose patients include a 10-year-old girl who has just returned from vacation two weeks prior. The exhausted girl lies on a bed amid weeping parents and grandparents. She suffers from a headache and muscle pain and has a 39.8 C fever, though it spiked higher before her arrival at the ED.

“Because symptoms for malaria can mimic other infectious diseases, clinicians need to be able to recognize it in order to ask the most appropriate questions,” she says.

Making real-time decisions

In the vignette, participants are asked to type additional questions to help with diagnosis. Then, they select one of three geographic regions to explore in the 20-minute module in order to gain a better appreciation of the epidemiology of malaria, including the Plasmodium species that cause disease in those regions; to recognize a patient with symptoms of malaria; and to manage their care in keeping with the CDC’s guidance.

Within a few clicks, participants select the degree of the girl’s parasitemia, view slides from thick and thin blood smears, choose the medicine best suited for the parasite causing illness and geographic region the family visited, and decide on follow-up care.

“The timed sections force decision-making in real-world situations,” Sestokas adds. “Behind the scenes, we can look at how well clinicians recognize the subtleties prior to making their decisions and we provide feedback in real-time. Ultimately, our goal is to stimulate deliberate, reflective practices.”

Rheumatic heart disease is a family affair

Parasternal long axis echocardiographic still frames in early systole in black and white and color Doppler of RHD-positive index case, sibling, and mother.

Parasternal long axis echocardiographic still frames in early systole in black and white and color Doppler of RHD-positive index case, sibling, and mother.

Siblings of children in Northern Uganda with latent rheumatic heart disease (RHD) are more likely to have the disease and would benefit from targeted echocardiographic screening to detect RHD before it causes permanent damage to their heart valves, according to an unprecedented family screening study.

RHD results from a cascade of health conditions that begin with untreated group A β-hemolytic streptococcal infection. In 3 percent to 6 percent of cases, repeat strep throat can lead to acute rheumatic fever. Almost half of children who experience acute rheumatic fever later develop chronic scarring of the heart valves, RHD.  RHD affects around 33 million people and occurs most commonly in low-resource environments, thriving in conditions of poverty, poor sanitation, and limited primary healthcare. Treating streptococcal infections can prevent a large percentage of children from developing RHD, but these infections are difficult to diagnose in low-resource settings.

Right now, kids with RHD often are not identified until they reach adolescence, when the damage to their heart valves is advanced and severe cardiac symptoms or complications develop. In such countries, cardiac specialists are rare, and intervention at an advanced stage is typically too expensive or unavailable.  Echocardiographic screening can “see” RHD before symptoms develop and allow for earlier, more affordable, and more practical intervention. A team led by Children’s National Health System clinicians and researchers conducted the first-ever family echocardiographic screening study over three months to help identify optimal strategies to pinpoint the families in Northern Uganda at highest RHD risk.

“Echocardiographic screening has the potential to be a powerful public health strategy to lower the burden of RHD around the world,” says Andrea Beaton, M.D., a cardiologist at Children’s National and the study’s senior author. “Finding the 1 percent of vulnerable children who live in regions where RHD is endemic is a challenge. But detecting these silent illnesses would open the possibility of providing these children monthly penicillin shots – which cost pennies and prevent recurrent streptococcal infections, rheumatic fever, and further valve damage.”

The research team leveraged existing school-based screening data in Northern Uganda’s Gulu District and recruited 60 RHD-positive children and matched them with 67 kids attending the same schools who were similar in age and gender but did not have RHD. After screening more than 1,000 parents, guardians, and first-degree family members, they found that children with RHD were 4.5 times as likely to have a sibling who definitely had RHD.

“Definite RHD was more likely to be found in mothers, with 9.3 percent (10/107 screened) having echocardiographic evidence of definite RHD, compared to fathers 0 percent (0/48 screened, p = 0.03), and siblings 3.3 percent (10/300 screened, p = 0.02),” writes lead author Twalib Aliku, School of Medicine, Gulu University, and colleagues. “There was no increased familial, or sibling risk of RHD in the first-degree relatives of RHD-positive cases (borderline & definite RHD) versus RHD-negative cases. However, RHD-positive cases had a 4.5 times greater chance of having a sibling with definite RHD (p = 0.05) and this risk increased to 5.6 times greater chance if you limited the comparison to RHD-positive cases with definite RHD (n = 30, p = 0.03.”

The paper, “Targeted Echocardiographic Screening for Latent Rheumatic Heart Disease in Northern Uganda,” was published recently by PLoS and is among a dozen papers published this year about the group’s work in Africa, done under the aegis of the Children’s Research Institute global health initiative.

The World Health Organization previously has prioritized screening household contacts when an index case of tuberculosis (TB) is identified, the authors note. Like TB, RHD has a strong environmental component in that family members are exposed to the same poverty, overcrowding, and circulating streptococcal strains. In a country where the median age is 15.5, it is not practical to screen youths without a detailed plan, Dr. Beaton says. Additional work would need to be done to determine which tasks to shift to nurses, who are more plentiful, and how to best leverage portable, hand-held screening machines.

“Optimal implementation strategies, the who, when, in what setting, and how often to screen, have received little study to date, yet these details are critical to developing cost-effective and sustainable screening programs,” Aliku and co-authors write. “Our study suggests that siblings of children identified with latent RHD are a high-risk group, and should be prioritized for screening.”

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