Pulmonology and Lung Surgery Research

Residents: Frontline defenders against antibiotic resistance?

September 22, 2017

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.”

Losing sleep: Severe obstructive sleep apnea

July 25, 2017

Researchers at Children’s National collected information on 250 children with severe obstructive sleep apnea – defined as at least 10 pauses in breathing in an hour during sleep – who were seen at Children’s National’s Pediatric Sleep Laboratory.

Obstructive sleep apnea (OSA) often starts with a snore that sounds harmless enough. But over time, explains Sasikumar Kilaikode, M.D., a pediatric pulmonary fellow in the Division of Pulmonary Care at Children’s National Health System, this condition can lead to serious health consequences. OSA, caused when the airway becomes periodically blocked during sleep, has a bevy of associated and often serious complications that can affect children, including heart problems and neurocognitive issues, such as learning disabilities.

“Many of the consequences of obstructive sleep apnea are preventable if patients get timely diagnosis and treatment,” Dr. Kilaikode says. “But we haven’t been sure how timely these interventions happen for some of our patients.”

Researchers have reported that conditions such as asthma and probably OSA tend to disproportionally affect children from disadvantaged backgrounds and that the severity of this condition tends to be greater in minority groups. However, Dr. Kilaikode explains, there have been insufficient data about how the most severe form of this condition affects inner city residents, a population that tends to have relatively higher numbers of disadvantaged, minority children – particularly the timeliness of diagnosis and treatment for this group.

To investigate, Dr. Kilaikode, his mentor Gustavo Nino Barrera, M.D., and colleagues collected information on 250 children with severe OSA – defined as at least 10 pauses in breathing in an hour during sleep – who were seen at Children’s National’s Pediatric Sleep Laboratory. This facility performs sleep studies on children during which their oxygen levels, breathing patterns, movements and brain activity are monitored while they snooze in a hospital bed overnight.

Besides their sleep study data, the researchers also collected information about:

Risk factors for OSA (such as enlarged tonsils or adenoids, craniofacial abnormalities, asthma, prematurity or obesity)
Demographics
Duration of symptoms before diagnosis by the overnight sleep study

The vast majority of the 250 children enrolled in the study were African American, reflective of the demographics of the hospital’s service area. The team was surprised to learn that the time to diagnosis for African American study participants was much longer than the time to diagnosis for the non-Latino white study participants.

The team presented these results at the American Thoracic Society 2017 International Conference in Washington, D.C.

“The longer patients take to get diagnosed and treated,” Dr. Kilaikode notes, “the more likely the serious consequences of OSA become permanent.”

He adds that it’s unclear why it took so long for some patients to be diagnosed – the team’s current research efforts are focused on this question. Some of their theories are that families and schools might be unaware of this condition and its symptoms; some families might have limited access to the health care system; probable lack of screening by primary care providers; or problems with health insurance might preclude timely or adequate care.

In the future, he and other members of the Children’s pulmonary team would like to focus OSA education and outreach efforts on people that this study suggests have the greatest need: Minority and low-income families. The first step, Dr. Kilaikode says, is helping families recognize symptoms early.

Symptoms of obstructive sleep apnea include:

Snoring
Choking, gasping or prolonged pauses in breaths during sleep
Daytime fatigue and/or sleepiness
Learning problems or difficulty concentrating at school

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

July 17, 2017

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.

PDE-5 inhibitors for pediatric hypertension

March 8, 2017

A study led by Chinwe Unegbu, M.D., indicates the benefits of PDE-5 inhibitors to treat pediatric pulmonary hypertension far outweigh potential harmful side effects.

Pulmonary hypertension (PH), when pressure in the blood vessels leading from the heart to the lungs is too high, is primarily a disease of adults: Patient registries suggest that the mean age of diagnosis is around age 50. However, more and more children are developing this condition, says Chinwe Unegbu, M.D., an assistant professor in the Division of Anesthesiology, Pain and Perioperative Medicine at Children’s National Health System.

Although adults with PH have several different effective treatments, Dr. Unegbu adds, children have few options. One of these is a class of medications known as phosphodiesterase type 5 (PDE-5) inhibitors, which act on molecular pathways that can open up constricted blood vessels. However, some studies have raised questions about the safety of this class of medications, particularly with long-term use of high dosages.

In a new study, Dr. Unegbu and colleagues performed a systematic review of available literature on this class of drugs evaluating their effectiveness and safety for pediatric patients. The review showed that like all medications, PDE-5 inhibitors have some risks. However, Dr. Unegbu says, the review showed that their benefits, including improved echocardiography measurements, cardiac catheterization parameters and oxygenation, far outweigh potential harmful side effects.

“Pediatricians across the nation view the rise in pediatric PH cases with growing concern because the disease can worsen, leading to right ventricular failure and death,” says Dr. Unegbu, lead author of the study. “PH can occur in newborns, infants and children who have a number of health conditions, including congenital heart disease, the most common birth defect among newborns. There are few available treatments for the growing population of children affected by this condition, so it is heartening that the evidence supports PDE-5 inhibitors for patients with PH.”

Patients with PH experience increased pressure in the pulmonary arteries, which carry blood from the heart to the lungs where it picks up oxygen that is ferried throughout the body. According to the National Institutes of Health, this leads patients to suffer from shortness of breath while doing routine tasks, chest pain and a racing heartbeat. Changes to the arteries make it progressively harder for the heart to pump blood to the lungs, which forces the heart to work even harder. Despite the heart muscle compensating by growing larger, less blood ultimately flows from the right to the left side of the heart which can compromise the kidney, liver and other organs, Dr. Unegbu says.

The study team included four researchers from Johns Hopkins University: Corina Noje, M.D., John D. Coulson, M.D., Jodi B. Segal, M.D., M.P.H., and study senior author Lewis Romer, M.D. The researchers scoured Medline, Embase, SCOPUS and the Cochrane Central Register of Controlled Trials, looking for studies that examined PDE-5 inhibitor use by pediatric patients with primary and secondary PH. Their goals included describing the nature and scale of the pediatric PH, assessing available pharmacologic therapies and conducting the systematic review of clinical studies of PDE-5 inhibitors, a mainstay of PH therapy.

They identified 1,270 studies. Twenty-one met the criteria to be included in the comprehensive review, including eight randomized controlled trials – the gold standard. The remaining 13 were observational studies in children ranging in age from extremely preterm to adolescence.

“Although there is some risk associated with PDE-5 inhibitor use by pediatric patients with PH, overwhelmingly the data indicate the benefits of using this class of drugs far outweigh the risks. When we looked at specific clinical outcomes, we see definite improvement in a number of measures including oxygenation, hemodynamics and better clinical outcomes: The patients are doing better, feeling better and their exercise capacity rises,” Dr. Unegbu says.

Because of lingering concerns about increased mortality, they also looked at toxicity data associated with this class of drugs. “With the exception of a single trial, the remaining trials included in our review did not demonstrate increased mortality in patients placed on this class of medicines, which was reassuring to us,” she says. Side effects ranged from mild to moderate, such as flushing and headaches. “We can say with a good degree of confidence that providers should feel fairly comfortable prescribing PDE-5 inhibitors.”

Ideally, researchers would like to have access to patient-specific measures that are a good fit for neonates and infants. Unlike adults, infants’ exercise capacity cannot be measured by their ability to climb stairs or use a treadmill. Another limitation, the study authors note, is the dearth of adequately powered clinical trials conducted in kids.

“Most of the studies have been conducted in adults. However, this disease unfolds in a much different fashion in children compared with adults,” Dr. Unegbu says. “We are desperately in need of high-quality studies in the form of randomized controlled trials in pediatric patients and studies that examine the full range of formulations of this class of drugs.”

Puzzling symptoms lead to collaboration

February 24, 2017

Sarah B. Mulkey, explaining the research

Sarah B. Mulkey, M.D., Ph.D., is lead author of a study that describes a brand-new syndrome that stems from mutations to KCNQ2, a genetic discovery that began with one patient’s unusual symptoms.

Unraveling one of the greatest mysteries of Sarah B. Mulkey’s research career started with a single child.

At the time, Mulkey, M.D., Ph.D., a fetal-neonatal neurologist in the Division of Fetal and Transitional Medicine at Children’s National Health System, was working at the University of Arkansas for Medical Sciences. Rounding one morning at the neonatal intensive care unit (NICU), she met a new patient: A newborn girl with an unusual set of symptoms. The baby was difficult to wake and rarely opened her eyes. Results from her electroencephalogram (EEG), a test of brain waves, showed a pattern typical of a severe brain disorder. She had an extreme startle response, jumping and twitching any time she was disturbed or touched, that was not related to seizures. She also had trouble breathing and required respiratory support.

Dr. Mulkey did not know what to make of her new patient: She was unlike any baby she had ever cared for before. “She didn’t fit anything I knew,” Dr. Mulkey remembers, “so I had to get to the bottom of what made this one child so different.”

Suspecting that her young patient’s symptoms stemmed from a genetic abnormality, Dr. Mulkey ran a targeted gene panel, a blood test that looks for known genetic mutations that might cause seizures or abnormal movements. The test had a hit: One of the baby’s genes, called KCNQ2, had a glitch. But the finding deepened the mystery even further. Other babies with a mutation in this specific gene have a distinctly different set of symptoms, including characteristic seizures that many patients eventually outgrow.

Dr. Mulkey knew that she needed to dig deeper, but she also knew that she could not do it alone. So, she reached out first to Boston Children’s Hospital Neurologist Philip Pearl, M.D., an expert on rare neurometabolic diseases, who in turn put her in touch with Maria Roberto Cilio, M.D., Ph.D., of the University of California, San Francisco and Edward Cooper, M.D., Ph.D., of Baylor College of Medicine. Drs. Cilio, Cooper and Pearl study KCNQ2 gene variants, which are responsible for causing seizures in newborns.

Typically, mutations in this gene cause a “loss of function,” causing the potassium channel to remain too closed to do its essential job properly. But the exact mutation that affected KCNQ2 in Dr. Mulkey’s patient was distinct from others reported in the literature. It must be doing something different, the doctors reasoned.

Indeed, a research colleague of Drs. Cooper, Cilio and Pearl in Italy — Maurizio Taglialatela, M.D., Ph.D., of the University of Naples Federico II and the University of Molise — had recently discovered in cell-based work that this particular mutation appeared to cause a “gain of function,” leaving the potassium channel in the brain too open.

Wondering whether other patients with this same type of mutation had the same unusual constellation of symptoms as hers, Dr. Mulkey and colleagues took advantage of a database that Dr. Cooper had started years earlier in which doctors who cared for patients with KCNQ2 mutations could record information about symptoms, lab tests and other clinical findings. They selected only those patients with the rare genetic mutation shared by her patient and a second rare KCNQ2 mutation also found to cause gain of function — a total of 10 patients out of the hundreds entered into the database. The researchers began contacting the doctors who had cared for these patients and, in some cases, the patients’ parents. They were scattered across the world, including Europe, Australia and the Middle East.

Dr. Mulkey and colleagues sent the doctors and families surveys, asking whether these patients had similar symptoms to her patient when they were newborns: What were their EEG results? How was their respiratory function? Did they have the same unusual startle response?

She is lead author of the study, published online Jan. 31, 2017 in Epilepsia, that revealed a brand-new syndrome that stems from specific mutations to KCNQ2. Unlike the vast majority of others with mutations in this gene, Dr. Mulkey and her international collaborators say, these gain-of-function mutations cause a distinctly different set of problems for patients.

Dr. Mulkey notes that with a growing focus on precision medicine, scientists and doctors are becoming increasingly aware that knowing about the specific mutation matters as much as identifying the defective gene. With the ability to test for more and more mutations, she says, researchers likely will discover more cases like this one: Symptoms that differ from those that usually strike when a gene is mutated because the particular mutation differs from the norm.

Such cases offer important opportunities for researchers to come together to share their collective expertise, she adds. “With such a rare diagnosis,” Dr. Mulkey says, “it’s important for physicians to reach out to others with knowledge in these areas around the world. We can learn much more collectively than by ourselves.”

Study reveals asthma phenotypes in inner-city children

October 10, 2016

What’s known

According to the Centers for Disease Control and Prevention, 8.6 percent of children across the nation, or 6.3 million kids, have asthma, a disease characterized by wheezing and coughing associated with airway obstruction, bronchial hyperresponsiveness, and inflammation of the airway. However, children with asthma with low socioeconomic status who live in inner cities experience a disproportionately high burden of illness. While treatment guidelines provide uniformity in managing allergy and allergic inflammation, such approaches may be misdirected when kids have asthma symptoms but lack allergy or allergic inflammation. Knowledge of distinct disease phenotypes can help to improve care.

What’s new

The Asthma Phenotypes in the Inner City study enrolled school-aged kids living in nine U.S. inner cities, including Washington, DC. The research team collected data about their asthma at the beginning of the one-year study and every two months as the kids’ asthma was managed according to accepted guidelines. Phenotypic analysis for 616 of these kids found their asthma clustered into five distinct groups. Cluster “A” was characterized by lower allergy, lower inflammation, and minimal symptoms. Fifteen percent of the kids fit within “A.” Another 15 percent of kids’ asthma fit within Cluster “B.” They had highly symptomatic asthma despite high step-level treatment and relatively low allergy and inflammation. Cluster “C” was distinguished by minimal symptoms, intermediate allergy and inflammation, and mildly impaired pulmonary physiology. Some 24 percent of kids fit within this group. The remaining kids fit within Cluster “D” or “E” and experienced progressively higher asthma and rhinitis symptoms as well as allergy and inflammation.

Questions for future research

Q: How does exposure to allergens, viruses, and irritants like tobacco smoke—taken individually as well as in combination—influence asthma severity and symptoms for these at-risk youths?
Q: What approaches to treatment might result from these studies?

Training kids developing immune systems to prevent wheezing

June 22, 2016

PDF Version

What’s Known
Some 6.3 million U.S. children younger than 18—or 8.6 percent of the nation’s kids—have asthma. The disease is characterized by an inflammation of the airways, and symptoms may be triggered by breathing in such allergens as animal dander, pollen, dust, or mold.

Once children experience early wheezing, changes begin in the architecture of their lungs, causing a thicker basement membrane, a thickening of the lining of the lungs, which can result in a heightened tendency for the airways in the lungs to become inflamed.

What’s New
Asthma and allergic diseases are thought to result from disordered development of the immune system, a process that begins in the womb. A paradigm-shifting multicenter clinical trial will enroll patients at eight locations, including Children’s National Health System, to provide the type of “immune system training” that infants would experience if they grew up in rural settings—where most children’s immune systems develop more normally. The five-year study funded by the National Heart, Lung, and Blood Institute will identify 1,000 babies aged 6 months to 18 months who are at risk for asthma to receive safe doses of an inactivated bacteria to help them develop more properly functioning immune systems. The University of Arizona Health Sciences in Tucson will lead the national research effort. Researchers will gauge whether infants randomly assigned to receive treatment suffer fewer respiratory symptoms than infants randomly assigned to receive placebo.

Questions for Future Research
Q: What will be the longer-term effects of preventing early wheezing? Will the children develop asthma less frequently?
Q: If intervention with young children occurs early enough to interrupt the disease cycle—preventing asthma, wheezing, and allergies—will they miss fewer days of school when they are older?
Q: Will families be willing to consistently follow the complex regimen necessary to administer the inactivated bacterial products on a long-term basis?

Source: Oral Bacterial Extracts (ORBEX): Primary Prevention of Asthma and Wheezing in Children.

Enroll in this clinical trial—https://clinicaltrials.gov/ct2/show/NCT02148796