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mother helping child with inhaler

Beta-lactam and microbial diversity in cystic fibrosis

mother helping child with inhaler

The study, published in the Journal of Investigative Medicine, examined the hypotheses that beta-lactam antibiotic PK and PD is associated with changes in richness and alpha diversity following treatment of a pulmonary exacerbations and determined associations between antibiotic PK, PD, antibiotic resistance and lung function.

Cystic fibrosis (CF) is a chronic lung disease that affects more than 30,000 people in the United States and 70,000 people worldwide. While this chronic disease is characterized by acute pulmonary exacerbations that are frequently treated with antibiotics, the impact of antibiotics on airway microbial diversity remains a critical knowledge gap.

A new study led by researchers at Children’s National Hospital found that beta-lactam antibiotic pharmacokinetic (PK) and pharmacodynamic (PD) target attainment during treatment is associated with suppressed recovery of microbial diversity, following a pulmonary exacerbation in children and adolescents with CF.

“By laying the groundwork for understanding how antibiotic PK may influence microbial diversity following pulmonary exacerbation, we hope to identify improved ways to guide antibiotic therapy in persons with CF,” says Andrea Hahn, M.D., M.S., an infectious diseases specialist at Children’s National and lead author of the study.

The study, published in the Journal of Investigative Medicine, examined the hypotheses that beta-lactam antibiotic PK and PD is associated with changes in richness and alpha diversity following treatment of a pulmonary exacerbations and determined associations between antibiotic PK, PD, antibiotic resistance and lung function.

“Beta-lactam antibiotics are frequently used to treat pulmonary exacerbations in persons with CF, yet are not routinely optimized,” says Dr. Hahn. “This study demonstrates the importance of beta-lactam PK’s on changes within the airway microbiome and provides context for care providers regarding the potential long-term impacts of antibiotic use in persons with CF, to ensure that we are optimizing therapy with each pulmonary exacerbation.”

Additional authors from Children’s National include: Aszia Burrell, Hollis Chaney, M.D.Iman Sami Zakhari, M.D.Anastassios Koumbourlis, M.D., M.P.H. and Robert Freishtat, M.D., M.P.H.

Andrea Hahn

Pediatric Research names Andrea Hahn, M.D., M.S., early career investigator

Andrea Hahn

“I am honored to be recognized by Pediatric Research and the Society of Pediatric Research (SPR) at large,” said Dr. Hahn. “SPR is an amazing organization filled with excellent scientists, and to be highlighted by them for my work is truly affirming.”

For her work on the impact of bacterial functional and metabolic activity on acute episodes of cystic fibrosis, the journal Pediatric Research recognized Andrea Hahn, M.D., M.S., as Pediatric Research’s Early Career Investigator.

Cystic fibrosis is an autosomal recessive genetic disease, affecting more than 70,000 people worldwide. The condition’s morbidity and mortality are recurrent and result in a progressive decline of lung function.

“I am honored to be recognized by Pediatric Research and the Society of Pediatric Research (SPR) at large,” said Dr. Hahn. “SPR is an amazing organization filled with excellent scientists, and to be highlighted by them for my work is truly affirming.”

The exact mechanisms of the bacteria that chronically infect the airway triggering acute cystic fibrosis episodes, also known as pulmonary exacerbations, remain unclear. Dr. Hahn’s research is one of the few to explore this gap and found an association with long-chain fatty acid production in cystic fibrosis inflammation.

“As a physician-scientist, there are many competing priorities between developing and executing good science — including writing manuscripts and grants — and providing excellent patient care both directly and through hospital-wide quality improvement initiatives,” said Dr. Hahn. “It is often easier to have successes and feel both effective and appreciated on the clinical side. This recognition of my scientific contributions to the medical community is motivating me to continue pushing forward despite the setbacks that often come up on the research side.”

The exposure to many programs and institutions gave Dr. Hahn the foundation to create a research program at Children’s National that helps decipher the complexities of antibiotic treatment and how it changes the airway microbiome of people with cystic fibrosis. The program also explores the impacts of antibiotic resistance and beta-lactam pharmacokinetics/pharmacodynamics (PK/PD) — the oldest class of antibiotics used to treat infections.

Dr. Hahn believes that the people and environment at Children’s National Hospital allowed her to grow and thrive as a physician-scientist.

“I was initially funded through an internal K12 mechanism, which was followed up by Foundation support, which was only possible because of the strong mentorship teams I have been able to build here at Children’s National,” said Dr. Hahn. “My division chief has also been very supportive, providing me with both protected time as well as additional resources to build my research lab.”

She is particularly appreciative of Robert Freishtat, M.D., M.P.H, senior investigator at the Center for Genetic Medicine Research, and Mary Callaghan Rose (1943-2016).

“Robert Freishtat has been a great advocate for me, and I am indebted to him for my success thus far in my career,” said Dr. Hahn. “Likewise, I want to specifically recognize Mary Rose. She was a great scientist at Children’s National until her death in 2016. She gave me the initial opportunity and support to begin a career studying cystic fibrosis, and she is missed dearly.”

You can learn more about Dr. Hahn’s research in this Pediatric Research article.

girl with cystic fibrosis getting breathing treatment

The role of long-chain fatty acids in cystic fibrosis inflammation

girl with cystic fibrosis getting breathing treatment

A recent study sheds light on the microbiologic triggers for lung inflammation and pulmonary exacerbations in cystic fibrosis.

Cystic fibrosis is an autosomal recessive disease that affects more than 70,000 people worldwide and results in a progressive decline of lung function. Patients with cystic fibrosis experience intermittent episodes of acute worsening of symptoms, commonly referred to as pulmonary exacerbations. While Staphylococcus aureus and Pseudomonas aeruginosa are thought to contribute to both lung inflammation and pulmonary exacerbations, the microbiologic trigger for these events remains unknown. Andrea Hahn, M.D., M.S., and her colleagues at Children’s National Hospital recently shed light on this matter by studying the changes in bacterial metabolic pathways associated with clinical status and intravenous (IV) antibiotic exposure in cystic fibrosis patients.

The researchers found increased levels of long-chain fatty acids (LCFAs) after IV antibiotic treatment in patients with cystic fibrosis. LCFAs have previously been associated with increased lung inflammation in asthma, but this is the first report of LCFAs in the airway of people with cystic fibrosis. This research indicates that bacterial production of LCFAs may be a contributor to inflammation in people with cystic fibrosis and suggests that future studies should evaluate LCFAs as predictors of pulmonary exacerbations.

Additional authors from Children’s National include: Hollis Chaney, M.D., Iman Sami Zakhari, M.D., Anastassios Koumbourlis, M.D., M.P.H. and Robert Freishtat, M.D., M.P.H.

Read the full study in Pediatric Research.

child using inhaler

The search for new Cystic Fibrosis clinical biomarkers

child using inhaler

Physician-scientists from Children’s National Hospital are unlocking new insights into Cystic Fibrosis by studying the type and number of bacteria in the lungs.

Cystic Fibrosis (CF) is a genetic disorder that chiefly affects the lungs and results in the production of abnormally dehydrated, viscous mucus. The inability to adequately clear this mucus leads to bacterial retention and both intermittent and chronic lung infections which require antibiotic therapy to treat. Researchers have used 16S rDNA amplicon sequencing for years in the attempts to characterize the airway microbiomes of CF patients, and more recently have used shotgun whole genome sequencing (WGS) techniques to obtain further details regarding bacterial species and strains. Previous studies on the airway microbiomes of CF patients have revealed that inter-person variability is high and can sometimes exceed intra-person variability. This can preclude generalizations regarding the CF population as a whole, which includes more than 30,000 Americans.

A recently published case study examined a young child with advanced and severely aggressive CF over a 12-month period, during which five pulmonary exacerbations occurred. A total of 14 sputum samples were collected across three clinical periods- baseline, exacerbation, and treatment. Samples were subsequently genetically sequenced (via 16s rDNA sequencing and, in three instances, WGS) and volatile metabolites were analyzed. The researchers hypothesized that if signature microbiome and metabolome characteristics correlated with one other and could be identified for each disease state, this data could serve as conglomerate biomarkers for the continuum of CF clinical states within an individual. In turn, this could inform future study design in a larger cohort.

Across all sputum samples, 109 individual operational taxonomic units (OTUs) and 466 distinct volatile metabolites were identified. 16s rDNA sequencing and WGS revealed that Escherichia coli and Staphylococcus aureus were the predominant bacteria during most baseline and exacerbation samples, despite some significant fluctuations in relative abundances. After the patient’s fifth antibacterial course, however, Achromobacter xylosoxidans became the new dominant bacterium.

Analysis revealed that the phylum Bacteroidetes and the genus Stenotrophomonas were significantly more abundant in treatment periods compared to baseline and exacerbation periods. WGS revealed the presence of bacteriophages as well as antibiotic resistance genes (mostly due to multi-drug resistance mechanisms), which can have important clinical ramifications and adds some dimensionality to the genetic analysis.

Volatile metabolite analysis found that observable fluctuations in metabolome composition coincided with fluctuations in the sputum microbiome. In this case, the microbiome and volatile metabolites produced by these bacteria provided an accurate assessment of the child’s clinical state. More specifically, the authors saw a distinct shift in both the microbiome and volatile metabolites with antibiotic treatment across the five independent pulmonary exacerbations. These additional assessments of the bacteria within the CF airway could provide an additional technique beyond standard bacterial cultures to better understand how the patient is responding to antibiotic treatment. Future studies in a larger group of children with CF may provide further insights into bacteria and volatile metabolite combinations that predict pulmonary exacerbation.

The article, “Longitudinal Associations of the Cystic Fibrosis Airway Microbiome and Volatile Metabolites: A Case Study,” was published in Frontiers in Cellular and Infection Microbiology. The lead author is Andrea Hahn, M.D., M.S., an investigator at the Children’s National Research Institute. Notable authors include Iman Sami, M.D., pulmonologist at Children’s National; Anastassios C. Koumbourlis, M.D., M.P.H, director of the Cystic Fibrosis Center; and Robert J. Freishtat, M.D., M.P.H, senior investigator at the Center for Genetic Medicine Research.

coronavirus

Study finds children can become seriously ill with COVID-19

coronavirus

Despite early reports suggesting COVID-19 does not seriously impact children, a new study shows that children who contract COVID-19 can become very ill.

In contrast to the prevailing view that the novel coronavirus known as COVID-19 does not seriously impact children, a new study finds that children who contract the virus can become very ill—many of them critically so, according to physician researchers at Children’s National Hospital. Their results, published in the Journal of Pediatrics and among the first reports from a U.S. institution caring for children and young adults, shows differences in the characteristics of children who recovered at home, were hospitalized, or who required life support measures. These findings highlight the spectrum of illness in children, and could help doctors and parents better predict which pediatric patients are more likely to become severely ill as a consequence of the virus.

In late 2019, researchers identified a new coronavirus, known as SARS-CoV-2, which causes COVID-19. As the disease spread around the world, the vast majority of reports suggested that elderly patients bear the vast majority of the disease burden and that children are at less risk for either infection or severe disease. However, study leader Roberta DeBiasi, M.D., M.S., chief of the Division of Infectious Diseases at Children’s National, states that she and her colleagues began noticing an influx of children coming to the hospital for evaluation of a range of symptoms starting in mid-March 2020, who were tested and determined to be infected with COVID-19. One quarter of these children required hospitalization or life support.

“It was very apparent to us within the first several weeks of the epidemic that this was a very different situation than our colleagues on the West Coast of the US had described as their experience just weeks before,” DeBiasi says. “Right away, we knew that it was important for us to not only care for these sick children, but to examine the factors causing severe disease, and warn others who provide medical care to children.”

To better understand this phenomenon, she and her colleagues examined the medical records of symptomatic children and young adults who sought treatment at Children’s National for COVID-19 between March 15 and April 30, 2020. Each of these 177 children tested positive using a rapid assay to detect SARS-CoV-2 performed at the hospital. The researchers gathered data on each patient, including demographic details such as age and sex; their symptoms; whether they had any underlying medical conditions; and whether these patients were non-hospitalized, hospitalized, or required critical care.

The results of their analysis show that there was about an even split of male and female patients who tested positive for COVID-19 at Children’s National during this time period. About 25% of these patients required hospitalization. Of those hospitalized, about 75% weren’t considered critically ill and about 25% required life support measures. These included supplemental oxygen delivered by intubation and mechanical ventilation, BiPAP, or high-flow nasal cannula – all treatments that support breathing – as well as other support measures such as dialysis, blood pressure support and medications to treat infection as well as inflammation.

Although patients who were hospitalized spanned the entire age range, more than half of them were either under a year old or more than 15 years old. The children and young adults over 15 years of age, Dr. DeBiasi explains, were more likely to require critical care.

About 39% of all COVID-19 patients had underlying medical conditions, including asthma, which has been highlighted as a risk factor for worse outcomes with this infection. However, DeBiasi says, although underlying conditions were more common as a whole in hospitalized patients – present in about two thirds of hospitalized and 80% of critically ill – asthma didn’t increase the risk of hospitalization or critical illness. On the other hand, children with underlying neurological conditions, such as cerebral palsy, microcephaly, or global developmental delay, as well as those with underlying cardiac, hematologic, or oncologic conditions were significantly more likely to require hospitalization.

In addition, although early reports of COVID-19 suggested that fever and respiratory symptoms are hallmarks of this infection, Dr. DeBiasi and her colleagues found that fewer than half of patients had both concurrently. Those with mild, upper respiratory symptoms, such as runny nose, congestion, and cough were less likely to end up hospitalized than those with more severe respiratory symptoms, such as shortness of breath. The frequency of other symptoms including diarrhea, chest pain and loss of sense of smell or taste was similar among hospitalized and non-hospitalized patients.

Dr. DeBiasi notes that although other East Coast hospitals are anecdotally reporting similar upticks in pediatric COVID-19 patients who become seriously ill, it’s currently unclear what factors might account for differences from the less frequent and milder pediatric illness on the West Coast. Some factors might include a higher East Coast population density, differences between the genetic, racial and ethnic makeup of the two populations, or differences between the viral strains circulating in both regions (an Asian strain on the West Coast, and a European strain on the East Coast).

Regardless, she says, the good news is that the more researchers learn about this viral illness, the better prepared parents, medical personnel and hospitals will be to deal with this ongoing threat.

Other researchers from Children’s National who participated in this study include Xiaoyan Song, Ph.D., M.Sc.Meghan Delaney, D.O., M.P.H.Michael Bell, M.D. Karen Smith, M.D.Jay Pershad, M.D., Emily Ansusinha, Andrea Hahn, M.D., M.S., Rana Hamdy, M.D., M.P.H., MSCE, Nada Harik, M.D.Benjamin Hanisch, M.D.Barbara Jantausch, M.D.Adeline Koay, MBBS, MS.c., Robin Steinhorn, Kurt Newman, M.D. and David Wessel, M.D.

Staphylococcus aureus

Understanding antibiotic resistance in patients with cystic fibrosis

Staphylococcus aureus

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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