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Staphylococcus

Airway microbial diversity in children with Cystic Fibrosis

Staphylococcus

Despite having less overall microbial richness, children with Cystic Fibrosis displayed a greater presence of Staphylococcus species.

Cystic Fibrosis (CF) is a disease that mainly affects the lungs and arises from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes for the CFTR membrane protein located on certain secretory cells. CFTR dysfunction leads to complications such as the production of abnormally viscous mucus which causes chronic suppurative lung infections that require antibiotics to treat. New drugs called CFTR modulators can help improve CFTR protein function and some are even FDA-approved for use in children. In addition to CFTR protein function, the lung’s resident microbiota and its richness of diversity, plays an important role in both health and disease, including CF.

In a new study published in Heliyon, scientists from Children’s National Hospital examined the difference in the upper airway microbiome between children with CF and healthy controls. Age-related differences among children with CF and the impact of CFTR modulators on microbial diversity were also assessed. Seventy-five children between 0-6 years of age participated in the study, including 25 children with CF and 50 healthy controls. For CF participants, oropharyngeal swabs and clinical data were obtained from the biorepository, while data for controls were obtained during a single clinical visit.

Analysis revealed that CF patients had less microbial diversity and different composition of the upper airway microbiome compared to age similar controls, a finding that is consistent with research on the lower airways. Despite having less overall microbial richness, children with CF displayed a greater presence of Staphylococcus species, (a main driver of the pulmonary exacerbations characteristic of CF), three Rothia operational taxonomic units (OTUs) and two Streptococcus OTUs. CF patients received a significantly higher number of antibiotics courses within the previous year compared to healthy controls, and further investigation will be necessary to understand the impact of antibiotics on the upper airway microbiome of infants and children with CF.

Longitudinal comparisons to study effects of age and CFTR modulation on the microbiome of children with CF were also undertaken. Younger CF patients (those 0 to <3 years of age at study enrollment), were more likely to have culturally-normal respiratory flora and more stable microbial composition over time than older CF patients (those ≥ 3–6 years of age at study enrollment), with no significant differences in alpha or beta diversity. Older CF patients were significantly more likely to be receiving a CFTR modulator than younger patients. CF patients receiving CFTR modulators had higher microbial diversity measures than those not receiving CFTR modulators and were closer (but still significantly lower) in microbial richness to healthy controls. No significant differences in beta diversity were found between the three groups.

This study adds to the growing body of evidentiary support for the use of CFTR modulators in improving airway microbial diversity in CF patients. Future studies with a larger cohort and greater focus on the impact on early initiation of CFTR modulators on microbial diversity and clinical outcomes is necessary.

The study, “Airway microbial diversity is decreased in young children with cystic fibrosis compared to healthy controls but improved with CFTR modulation,” was recently published in Heliyon. The lead author is Andrea Hahn, M.D., M.S., an investigator at the Children’s National Research Institute. Notable authors include Aszia Burrell; Emily Ansusinha; Hollis Chaney, M.D.; Iman Sami, M.D.; Geovanny F. Perez, M.D.; Anastassios C. Koumbourlis, M.D., M.P.H.; Robert McCarter, Sc.D.; and Robert J. Freishtat, M.D., M.P.H..

Robin Steinhorn in the NICU

Coming together as a team for the good of the baby

Robin Steinhorn in the NICU

Children’s National has a new program to care for children who have severe bronchopulmonary dysplasia, a serious complication of preterm birth.

Around the 1-year-old’s crib is a tight circle of smiling adults, and at the foot of his bed is a menagerie of plush animals, each a different color and texture and shape to spark his curiosity and sharpen his intellect.

Gone are the days a newborn with extremely complex medical needs like Elijah would transfer from the neonatal intensive care unit (NICU) to the pediatric intensive care unit and transition through a couple of other hospital units by the time he was discharged. Gone are the days when he’d see a variety of new physician faces at every stop. And gone are the days he’d be confined to his room, divorced from the sights and sounds and scents of the outside world, stimulation that helps little baby’s neural networks grow stronger.

Children’s National has a new program designed to meet the unique needs of children like Elijah who have severe bronchopulmonary dysplasia (BPD), a common complication of preterm birth.

“It’s more forward-thinking – and I mean thinking for the future of each individual baby, and it’s allowing the baby to have one team and one location to take advantage of a deep knowledge of and relationship with that baby and family,” says Robin Steinhorn, M.D. Dr. Steinhorn is senior vice president of the Center for Hospital-Based Specialties and one of Children’s multidisciplinary team members who visited Elijah’s bed twice weekly during his lengthy hospitalization and who continues to see him regularly during outpatient visits.

“The pulmonologist, the neonatologist, the respiratory therapist, the physical therapist, the dietitian, the cardiologist – we all come as a team to work together for the good of the baby,” Dr. Steinhorn adds. “We stick with these babies through thick and thin. We will stick with that baby with this team and this location until they are ready to go home – and beyond.”

BPD, a serious lung condition, mostly affects extremely low birthweight preterm babies whose lungs were designed to continue developing inside the womb until the pregnancy reaches full term. Often born months before their due dates, these extremely vulnerable newborns have immature organs, including the lungs, which are not ready for the task of breathing air. Children’s program targets infants who experience respiratory failure from BPD. The respiratory support required for these infants ranges from oxygen delivered through a nasal cannula to mechanical ventilators.

Robin Steinhorn and Colleague

“It’s more forward-thinking – and I mean thinking for the future of each individual baby, and it’s allowing the baby to have one team and one location to take advantage of a deep knowledge of and relationship with that baby and family,” says Robin Steinhorn, M.D.

About 1 percent of all preterm births are extremely low birthweight, or less than 1,500 grams. Within that group, up to 40 percent will develop BPD. While they represent a small percentage of overall births, these very sick babies need comprehensive, focused care for the first few years of their lives. And some infants with severe BPD also have pulmonary hypertension which, at Children’s National, is co-managed by cardiology and pulmonary specialists.

Children’s BPD team not only focuses on the child’s survival and medical care, they focus on the neurodevelopmental and social care that a baby needs to thrive. From enhanced nutrition to occupational and physical therapy to a regular sleep cycle, the goal is to help these babies achieve their full potential.

“These babies are at tremendous risk for long-term developmental issues. Everything we do is geared to alleviate that,” adds John T. Berger III, M.D., director of Children’s Pulmonary Hypertension Program.

“Our NICU care is more focused, comprehensive and consistent,” agrees Mariam Said, M.D., a neonatologist on the team. “We’re also optimizing the timing of care and diagnostic testing that will directly impact health outcomes.”

Leaving no detail overlooked, the team also ensures that infants have age-appropriate developmental stimuli, like toys, and push for early mobility by getting children up and out of bed and into a chair or riding in a wagon.

“The standard approach is to keep the baby in a room with limited physical or occupational therapy and a lack of appropriate stimulation,” says Geovanny Perez, M.D., a pulmonologist on the team. “A normal baby interacts with their environment inside the home and outside the home. We aim to mimic that within the hospital environment.”

Dr. Steinhorn, who had long dreamed of creating this comprehensive team care approach adds that “it’s been so gratifying to see it adopted and embraced so quickly by Children’s NICU caregivers.”

Anastassios Koumbourlis

Challenging the diagnostic criteria for pediatric asthma

Anastassios Koumbourlis

Recent research by Anastassios Koumbourlis, M.D., M.P.H, and colleagues challenges the use of the term physician-diagnosed asthma (PDA).

Children’s National physicians Anastassios Koumbourlis, M.D., M.P.H, division chief of Pulmonary and Sleep Medicine, and Geovanny Perez, M.D., attending pulmonologist and asthma researcher, co-authored a recent article published in the Annals of the American Thoracic Society entitled “Heterogeneity in the Diagnostic Criteria Physicians use in Pediatric Asthma.” Their study focused on the term “physician-diagnosed asthma” (PDA) that is commonly used, especially in research, as a specific characteristic that allow the stratification of patients to different groups (e.g. those with PDA vs. those without PDA). The term simply means that a patient has been given the diagnosis of asthma by a physician without any explanation as to how the diagnosis was made. Drs. Koumbourlis and Perez challenge the validity of the term on the grounds that “asthma is often misdiagnosed, because there are no consistencies in the criteria physicians use to make the diagnosis.”

To prove their theory, a survey was sent to pediatric pulmonologists and general pediatricians to identify the clinical and laboratory criteria they use to diagnose pediatric asthma. The responses were tabulated separately for the two groups. In total, 205 pediatric pulmonologists from 24 different countries and 111 general pediatricians responded to the survey.

The results revealed substantial variability between pulmonologists and general pediatricians:

  • “‘Resolution of symptoms after treatment with bronchodilators’ was the most frequently (85 percent) chosen criterion by pulmonologists, followed by ‘symptoms on exertion’ and ‘recurrent/persistent cough in the absence of infection’ (55 percent and 35 percent, respectively). Non-pulmonologists chose equally the presence of ‘symptoms on exertion’ and the ‘resolution of symptoms with bronchodilators’ (76 percent and 74 percent, respectively), followed by ‘recurrent/persistent cough’ (38 percent).
  • “There were striking differences in the use of diagnostic tests between the two groups. Almost all pulmonologists (91 percent) chose spirometry before and after the bronchodilator as part of their diagnosis. They were also significantly more likely to use other tests. In contrast, two-thirds of the non-pulmonologists (64 percent) do not use any tests.”

The results of the survey reveal noteworthy discrepancies not only between practice and guidelines, but more importantly between physicians, often determined by their specialty. This variability in the diagnostic criteria for asthma means that patients who are assigned as having PDA do not necessarily represent a homogeneous population. This, in turn, may significantly affect the results of research studies that use the term PDA to categorize patients into different groups. Thus, the investigators conclude, the term PDA should either be avoided completely or, if it must be used, it should be accompanied by the specific criteria on which the diagnosis was based.

Gustavo Nino

New method may facilitate childhood respiratory research

Gustavo Nino

“The use of CRC is a potentially powerful translational approach to shed light on the molecular mechanisms that control airway epithelial immune responses in infants and young children. This novel approach enables us to study the origins of respiratory disease and its chronic progression through childhood and beyond,” observes Gustavo Nino, M.D., a Children’s pulmonologist and study senior author.

A new method perfected by a team at Children’s National Health System may help expand research into pulmonary conditions experienced by infants and children, an understudied but clinically important age group. The study describing the new technique was published in the December 2017 print edition of Pediatric Allergy and Immunology.

Using conditionally reprogrammed cells (CRCs), a technique that enables indefinite proliferation of cells in the lab, the team was able to produce cell cultures that have a number of advantages over standard cultures and that may make it easier and more efficient to conduct research into pediatric respiratory immune responses.

The epithelial cells that line human airways are crucial in controlling immune responses to viruses, allergens and other environmental factors. The function and dysfunction of these airway epithelial cells (AECs) play a key role in asthma, cystic fibrosis and other pulmonary conditions, many of which begin in early life.

To generate enough of these cells for research, scientists culture AECs from primary nasal and bronchial cell samples. Cells derived from adults have fueled research leading to new therapies and the discovery of key biomarkers. But little comparable research has been conducted in infants. Airway sampling in premature infants has not been reported, likely to due to airway size limitations and underlying comorbidities. Similarly, sampling in infants is limited by the need for bronchoscopy and sedation.

“A major barrier has been the lack of a good system to culture epithelial cells, since airway sampling in infants and children is a challenge,” says co-lead author, Geovanny F. Perez, M.D., co-director of Children’s Severe Bronchopulmonary Dysplasia Program. “We needed a better way to culture cells in this age group.”

While primary AECs do not survive long in the lab, that hurdle was recently overcome by a process that generates CRCs from the primary AECs of adults, making it possible to quickly generate cell cultures from specimens.

In this study, the Children’s team adapted that approach, producing CRCs from primary AECs of neonates and infants. The CRC induction successfully enabled AEC cultures from infants born prematurely and from bronchial specimens of young children.

Geovanny Perez

“A major barrier has been the lack of a good system to culture epithelial cells, since airway sampling in infants and children is a challenge,” says co-lead author, Geovanny F. Perez, M.D., co-director of Children’s Severe Bronchopulmonary Dysplasia Program. “We needed a better way to culture cells in this age group.”

“We found that the CRCs have longer cell life and greater proliferation ability than standard cultures of epithelial cells. They preserved their original characteristics even after multiple experiments. And, they presented an innate immune response similar to that seen in primary human epithelial cells during viral respiratory responses in children,” says Dr. Perez.

“The use of CRC is a potentially powerful translational approach to shed light on the molecular mechanisms that control airway epithelial immune responses in infants and young children. This novel approach enables us to study the origins of respiratory disease and its chronic progression through childhood and beyond,” observes Gustavo Nino, M.D., a Children’s pulmonologist and study senior author.

The authors note that further studies are needed to define more precisely the differences and similarities in the immune responses of CRC and non-CRC derived from primary AEC. However, they conclude that CRC represents a new, effective method to study AEC innate immune responses in infants.

In addition to Drs. Perez and Nino, Children’s Center for Genetic Medicine Research co-authors include Co-Lead Author S. Wolf; Lana Mukharesh; Natalia Isaza Brando, M.D.; Diego Preciado, M.D., Ph.D.; Robert J. Freishtat, M.D., M.P.H.; Dinesh Pillai, M.D.; and M. C. Rose.

Financial support for this research was provided by the National Institute of Allergy and Infectious Diseases under grant number R21AI130502; Eunice Kennedy Shriver National Institute of Child Health and Human Development under grant number HD001399; National Heart, Lung and Blood Institute under grant number HL090020; and National Center for Advancing Translational Sciences under grant number UL1TR000075.

Human Rhinovirus

When a common cold may trigger early supportive care

Human Rhinovirus

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

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

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

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

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

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

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

Geovanny Perez

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

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

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

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

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

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

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

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

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

Unlocking the ‘black box’ of NICU monitors to protect vulnerable preemies

MiningdatafromNICUmonitors

What’s Known
Around the world, some 15 million infants are born prematurely each year. Babies born prematurely can spend their first weeks to months of life in the neonatal intensive care unit (NICU) tethered to machines that closely monitor vital signs, such as breathing and heart rate.

After discharge, preemies have a very high risk of returning to the NICU, often due to breathing difficulties, such as experiencing excessively long pauses between breaths. Such acute life-threatening events are a major cause of preemies’ hospital readmission and may result in death.

What’s New
During infants’ NICU stays, cardiorespiratory monitors amass a mountain of data about each child. Through the unprecedented collaboration of researchers working in various divisions of Children’s National Health System, the team was able to unlock that black box of information by creating algorithms to extract data and by using retrospective analyses to tease out new insights. This multidisciplinary team has been able to predict with a greater degree of precision which babies are at higher risk of returning to the NICU after discharge. What these most vulnerable preemies have in common is the degree of maturation of their autonomic nervous system, which controls such involuntary actions as heart rate and breathing. The sympathetic nervous system, which the body leverages as it copes with the stress of life-threatening events (ALTE), also plays a role in these infants’ heightened vulnerability. Being able to identify these newborns earlier has the potential to lower readmissions and save lives.

Questions for Future Research
Q: How can further computer-based analyses of NICU monitor data be used to determine how preemies respond to routine activities, such as feeding to predict which infants have compromised cardiorespiratory systems?
Q: How can we develop a test to assess all premature infants for physiologic readiness for safe NICU discharge and, thus, prevent ALTE and sudden death in this vulnerable population?

Source: Vagal Hypersensitivity in Premature Infants and Risk of Hospital Readmission Due to Acute Life-Threatening Events (ALTE).” G. Nino, R. Govindan, T. AlShargabi, M. Metzler, R. Joshi, G. Perez, A.N. Massaro, R. McCarter, and A. du Plessis. Presented during the 2016 Pediatric Academic Societies Annual Meeting, Baltimore, MD. May 2, 2016.