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Impact of anaerobic antibacterial spectrum on cystic fibrosis

Researchers from Children’s National Hospital found that broad spectrum antianaerobic therapy had greater and longer lasting effects on the lung microbiome of persons with cystic fibrosis.

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the chloride ion channel encoding CF transmembrane conductance regulator gene, leading to multiple morbidities and early mortality. In a new clinical study, researchers from Children’s National Hospital found that broad spectrum antianaerobic therapy had greater and longer lasting effects on the lung microbiome of persons with CF.

They found this difference when comparing the microbiology and clinical outcomes in children with CF who were treated with “broad” or “narrow” antianaerobic antibiotics for exacerbations of their disease. While there are many factors that determine whether “narrow” or “broad” spectrum antibiotics are used, the data showed that the recovery of pulmonary function was similar between those groups.

“The findings prove that most providers are following best practices when treating patients with cystic fibrosis using the narrowest spectrum of antibiotics possible, and reserving broad spectrum agents for more advanced disease when culture data shows more resistant bacteria,” says  Michael Bozzella, the study’s lead author.

The study, published in the Pediatric Infectious Disease Journal, analyzed how the spectrum of antibiotics prescribed to patients with cystic fibrosis impacts the population of bacteria in their lungs how it ties back to lung function.

“Research like this improves antibiotic and antimicrobial stewardship,” said Bozzella. “When speaking with families and patients with cystic fibrosis, providers can be more aware of the relationship between lung microbiome, disease state, and antibiotics and create more holistic treatment plans.”

Dr. Bozzella did this research as a fellow at Children’s National and he’s now an Infectious Disease Attending Physician at Children’s Hospital Colorado. Additional authors from Children’s National include: Andrea Hahn, M.D., M.S., Hollis Chaney, M.D.Iman Sami Zakhari, M.D.Anastassios Koumbourlis, M.D., M.P.H. and Robert Freishtat, M.D., M.P.H.

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.

Francis Collins

Francis S. Collins, M.D., Ph.D. from NIH: The future of genomic medicine and research funding opportunities

Kurt Newman and Francis Collins

Genomic medicine, diversity, equity and inclusion (DEI), a world post-COVID-19 and pediatric research funding were among the topics discussed during the “Special Fireside Chat” keynote lecture at the 2021 Children’s National Hospital Research, Education and Innovation Week.

Francis S. Collins, M.D., Ph.D., director at the National Institutes of Health (NIH), is well known for his landmark discoveries of disease genes and his leadership of the international Human Genome Project, which culminated in April 2003 with the completion of a finished sequence of the human DNA instruction book.

The President and CEO of Children’s National, Kurt Newman, M.D., joined Dr. Collins during the “Special Fireside Chat” keynote lecture. Dr. Newman posed several health care-related questions to Dr. Collins over the course of 30 minutes. Dr. Collins’s responses shed light on what it takes to advance various research fields focused on improving child health and develop frameworks that advocate for DEI in order to foster a more just society.

Q: You have been involved with genomic medicine since its inception. You discovered the gene causing cystic fibrosis and led the Human Genome project. What do you see as the future of genomic medicine, especially as it relates to improving child health?

A: Thank you for the question, Kurt. First, I wanted to say congratulations on your 150th anniversary. Children’s National Hospital has been such a critical component for pediatric research and care in the Washington, D.C., area, and at the national and international levels. We at the NIH consider it a great privilege to be your partner in many of the things that we can and are doing together.

Genomic medicine has certainly come a long way. The word genomics was invented in 1980, so we have not been at this for that long. Yet, the success of the Human Genome Project and the access to cost-effective tools for rapid DNA sequencing have made many things possible. It took a lot of effort, time and money to discover the gene that causes cystic fibrosis. Kurt, if you look at what we did, while it was rewarding, it was a challenging problem that occupied the hearts of the scientific community in 1980. Now, a graduate student at Children’s National that has access to DNA samples, a thermal cycler, a DNA sequencer and the internet could do in about a week what it took us a decade and with 50 people.

We have been able to rocket forward as far as identifying the genetic causes of 6,500 diseases, where we know precisely the molecular glitch responsible for those conditions. While most of those are rare diseases, it leads to the opportunity for immediate diagnosis, which used to be a long and troubled journey.

DNA sequencing has increasingly become an essential tool in newborns, especially when trying to sort out puzzling diagnosis for specific syndromes or phenotypes that are not immediately clear. Additionally, DNA sequencing significantly impacted clinical care in cancer because it made it possible to look at the mutations driving the malignancy and its genetic information that can lead to interventions. This approach is going forward in the next few years in ways that we can see now. Although I am a little reluctant to make predictions because I have to be careful about that, it may be possible to obtain complete genome sequences that can be yours for life and place them into the medical record to make predictions about future risks and choices about appropriate drugs. This path costs less than any imaging tests.

Q: The racial justice movement that was brought back to the forefront this past year has, once again, reaffirmed that this country has so much more work to do in order to end systemic racism. You have been at the forefront of promoting diversity, equity and inclusion in research and at the NIH. What do you and the NIH plan to do further DEI efforts in research and in general so that we can be a more just and equitable society?

A: I appreciate you raising this, Kurt. Diversity, equity and inclusion (DEI) is an issue where everyone should be spending a lot of time, energy and passion. You are right. 2020 will be remembered for COVID-19. I also think it will be remembered for the things that occurred around the killing of George Floyd, and the recognition of the very foundation that is still infected by this terribly difficult circumstance of structural racism. I convened a group of about 75 deep thinkers about these issues, many of them are people of color from across the NIH’s different areas of activities. I asked the group to come forward with a bold set of proposals. This effort is how the program UNITE came together to work hard on this, which is now making recommendations that I intend to follow. We are determined to close that gap and pursue additional programs that will allow us to be more successful in recruiting and retaining minority groups, for example. We need to do something with our health disparity and research portfolio as well to ensure that we are not just looking around the edges of the causes for racial inequities. We are digging deeper into what the structural racism underpinnings are and what we can do about it. I am particularly interested in supporting research projects that test intervention and not just catalog the factors involved. We have been, at times, accused and maybe rightly so of being more academic about this, and, less kindly, we have been accused of admiring the problem of health disparities as opposed to acting on it. We are ready to act.

Q: COVID has affected us all in so many ways. Could you tell us what this past year has been like for you? Also, how is the NIH preparing for a soon-to-be post-COVID pandemic?

A: This is the time to contemplate the lessons learned as everyone knows that the last worst pandemic happened over a century ago. One thing that maybe will vex us going forward, which we already started to invest in a big way, is this whole long COVID syndrome, also referred to post-acute sequelae, to understand precisely the consequences and mechanisms like Multisystem Inflammatory Syndrome in Children (MIS-C). Before moving to the next pandemic, we must think about how we will help understand those who suffer from long COVID syndrome. As far as the broader lessons learn, Kurt, we must expect that there will be other pandemics because humans are interacting more with animals, so zoonosis is likely to emerge. We need to have a clear sense of preparation for the next one. For instance, we are working on this right now, but we need to have a stronger effort to develop small molecules of anti-viral drugs aimed at the major viral classes, so we do not have to start from scratch. We also need clinical trial networks warm all the time, ready to go and to learn how valuable public partnerships can be to get things done in a hurry.

Editor’s Note: The responses in this Q+A have been modified to fit the word count.

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.

woman writing data to medical form and glucometer for checking sugar level

New grant to assess screening tools for cystic fibrosis-related diabetes

woman writing data to medical form and glucometer for checking sugar level

A grant from the Cystic Fibrosis Foundation will help Children’s National researchers assess the feasibility and accuracy of two new cystic fibrosis-related diabetes screening tools.

Cystic fibrosis-related diabetes (CFRD) is the most common non-pulmonary manifestation of cystic fibrosis (CF), affecting up to 30% of adolescents and 50% of adults living with CF, according to the Cystic Fibrosis Foundation (CFF). CFRD is often asymptomatic and so the CFF recommends that people living with CF be screened for CFRD annually starting at 10 years of age using an oral glucose tolerance test.

Although early detection and treatment of CFRD can lead to significant clinical improvements and prolong life, rates of screening are poor, likely due to the burdensome nature of oral glucose tolerance testing (OGTT). Rates of OGTT screening in patients 10-17 years of age vary widely among CF care centers, ranging 5.9% to 100% with a median of 61.3% of patients at a given center completing screening. At Children’s National, only 46.4% of pediatric CF patients without CFRD completed the OGTT in 2019.  The most commonly cited reason for failure to complete recommended OGTT screening is the additional burden that this time-consuming fasting test, requiring three blood draws, places upon patients who already contend with multiple medical interventions.

“People living with CF face tremendous medical burdens.,” says Brynn Marks, M.D., MSHPEd, pediatric endocrinologist at Children’s National Hospital. “Novel, more convenient approaches to CFRD screening that can provide both diagnostic and therapeutic information are urgently needed.”

Dr. Marks and Carol Chace, MSW, a social worker at Children’s National, have collaborated to receive a $160,000 Pilot and Feasibility Award from the CFF that will allow researchers to assess the feasibility and accuracy of two new CFRD screening tools, the Dexcom G6 Pro, a continuous glucose monitoring (CGM), and the Digostics GTT@home, a home-based OGTT kit. The Dexcom G6 Pro is the first unblinded professional CGM that enables patients to see their glucose values and trends in real-time. The GTT@home uses a built-in timer and audio-visual cues to guide users to collect capillary blood samples through finger sticks.

“While the idea of home-based testing is exciting in general, it is particularly important in the midst of the COVID-19 pandemic, as many are limiting preventative health care visits,” says Dr. Marks. “This research will hopefully inform future larger studies that could one day allow for this screening to be done at home.”

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..

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.

Michael Tsifansky

Lung transplant expert Michael Tsifansky, M.D., F.A.A.P., joins Children’s

Michael Tsifansky

Earlier this year Michael Tsifansky, M.D., F.A.A.P., joined Children’s National Hospital as an attending physician in the Cardiac Intensive Care Unit and in the Division of Pulmonology and Sleep Medicine. He brings to Children’s National a unique mix of expertise in critical care and pulmonary medicine. That passion for these two subspecialties has also made him one of the country’s leading experts in lung transplant procedures and the recovery from them.

Dr. Tsifansky shared more information about caring for patients with complex lung diseases, especially those with end-stage lung disease. He outlines the patient population for pediatric lung transplants and the arduous process patients endure while waiting for a transplant, undergoing this major procedure, and then recovering from it.

What types of patients undergo lung transplant surgeries?

Lung transplantation in children is indicated when the following criteria are met:

  • End-stage lung disease
  • No reasonable alternative to the established diagnosis
  • No medical or surgical alternative to the current course of treatment
  • No other organ failure
  • Stable social environment

Could you describe the surgery process?

Pediatric lung transplantation may be performed on cardiopulmonary bypass, on extracorporeal membrane oxygenation (ECMO) or off extracorporeal cardiopulmonary support (ECS). The donor’s lungs are kept chilled prior to transplantation and should be transplanted within six to eight hours after removal from the donor. The donor’s main-stem bronchi and pulmonary arteries are connected to those of the recipient, and the donor’s pulmonary venous drainage is connected to the recipient’s left atrium using the donor’s left atrial roof tissue. This procedure typically takes six to eight hours.

Could you describe the recovery process?

Typically, pediatric lung transplant recipients are extubated and encouraged to sit up four to six hours after the transplant procedure and walk soon afterward. It is important that they be out of bed and moving as soon as possible, and our colleague from Rehabilitation Services (physical and occupational therapists and rehabilitation physicians) will be working with the children toward these goals. After transplantation, pediatric patients will be given discharge instructions with individualized guidelines for a healthy lifestyle. Patients should return to near-normal life approximately three to six months after transplantation.

How long does the recovery process take?

The patient will remain hospitalized for 11-14 days following surgery for acute rehab, titration of antirejection meds and initial healing.

You’ve mentioned that it’s important for transplant patients to get moving as part of recovery. When can a patient begin walking again?

Lung recipients will be assisted into a chair soon after the transplant. Within the first 24-36 hours, the patient is encouraged to take short walks, increasing the distance each day. A physical therapist will work with the patient during their hospitalization to meet their goals. We also encourage patients to exercise on the treadmill regularly while hospitalized. By the time the patient is ready to go home, he or she will be able to easily move around by themselves and do most of their care without assistance. They feel so much better than before transplant and have so much energy that we almost always have to gently limit their activity for a short while to allow their chest incision to heal properly.

What do you see as the next step in pulmonary care for end stage lung disease at Children’s National Hospital?

The development of a pediatric-specific lung transplant and respiratory failure program is the natural extension of the hospital’s cystic fibrosis program, heart transplant program and programs in pulmonary hypertension, bronchopulmonary dysplasia and extracorporeal membrane oxygenation for respiratory failure.

At present, there is no local option for a pediatric-specific program that can perform the transplant and provide the necessary comprehensive wrap-around services for patients in infancy up to age 18. As a top children’s hospital, Children’s National is uniquely positioned to provide the highest level of pediatric-specific care to this patient population and allow patients and their families to spend more time at home while undergoing this and other lifesaving treatments.

Dr. Tsifansky hopes to launch a comprehensive pediatric lung transplant and respiratory failure program at Children’s National in the very near future. Stay tuned for future developments from this area.

Pulmonary Medicine at Children's National

2019 at a glance: Pulmonary Medicine at Children’s National

Pulmonary Medicine at Children's National
E coli bacteria

Urinary bacteria in spinal cord injury cases may tip balance toward UTIs

E coli bacteria

Patients with spinal cord injuries nearly universally have bacteria present in their urine regardless of whether they have a urinary tract infection.

The fallout from spinal cord injury doesn’t end with loss of mobility: Patients can have a range of other issues resulting from this complex problem, including loss of bladder control that can lead to urine retention. One of the most serious implications is urinary tract infections (UTIs), the most common cause of repeat hospitalization in people with spinal cord injuries, explains Hans G. Pohl, M.D., associate chief in the division of Urology at Children’s National Health System.

Diagnosing UTIs in people with spinal cord injuries is trickier than in people who are otherwise healthy, Dr. Pohl explains. Patients with spinal cord injuries nearly universally have bacteria present in their urine regardless of whether they have a UTI. It’s unclear whether these bacteria are innocent bystanders or precursors to UTIs in patients who don’t yet show symptoms. And although antibiotics can wipe out this bacterial population, these drugs can have undesirable side effects and frequent use can promote development of antibiotic-resistant bacteria.

Although clinical dogma has long promoted the idea that “healthy” urine is sterile, Dr. Pohl and colleagues have shown that a variety of bacteria live in urine, even in people without symptoms. These microorganisms, like the intestinal microbiome, live in harmony with their hosts and may even help promote health. However, it’s unclear what this urinary microbiome might look like for patients with spinal cord injury before, during and after UTIs.

To start investigating this question, Dr. Pohl and co-authors recently reported a case study they published online Sept. 21, 2018, in Spinal Cord Series and Cases. The case report about a 55-year-old man who had injured the thoracic segment of his spinal cord—about the level of the bottom of his shoulder blades—in a skiing accident when he was 19 was selected as “Editor’s Choice” for the journal’s October 2018 issue.  The patient had a neurogenic bladder, which doesn’t function normally due to impaired communication with the spinal cord. To compensate for this loss of function, this patient needed to have urine removed every four to six hours by catheterization.

Over eight months Dr. Pohl, the study’s senior author, and colleagues collected 12 urine samples from this patient:

  • One was collected at a time the patient didn’t show any symptoms of a UTI
  • Nine were collected when the patient had UTI symptoms, such as bladder spasticity
  • Two samples were collected when the patient had finished antibiotic treatment for the UTI.

The researchers split each sample in half. One part was put through a standard urinalysis and culture, much like what patients with a suspected UTI would receive at the doctor’s office. The other part was analyzed using a technique that searched for genetic material to identify bacteria that might be present and to estimate their abundance.

The researchers found a variety of different bacteria present in these urine samples. Regardless of the patient’s health status and symptoms, the majority of these bacterial species are known to be pathogenic or potentially pathogenic. By contrast, this patient’s urine microbiome appeared to largely lack bacterial species known to be either neutral or with potentially probiotic properties, such as Lactobacillus.

All of the bacteria that grew in culture also were identified by their genetic material in the samples. However, genetic sequencing also identified a possible novel uropathogenic species called Burkholderia fungorum that didn’t grow in the lab in five of the samples. This bacterium is ubiquitous in the environment and has been identified in soil- and plant-based samples. It also has been discovered in the respiratory secretions of patients with cystic fibrosis, in patients with a heart condition called infectious endocarditis, in the vaginal microbiota of patients with bacterial vaginosis, and in the gut of patients with HIV who have low T-cell counts. Dr. Pohl says it’s unclear whether this species played an infectious role in this patient’s UTI or whether it’s just part of his normal urine flora.

“Consistent with our previous work, this case report demonstrates that rather than healthy urine being sterile, there is a diverse urine bacterial ecosystem during various states of health and disease,” Dr. Pohl says. “Rather than UTIs resulting from the growth or overgrowth of a single organism, it’s more likely that a change in the healthy balance of the urine ecosystem might cause these infections.”

By monitoring the relative abundance of different bacteria types present in the urine of patients with spinal cord injury and combining this information with a patient’s symptoms, Dr. Pohl says doctors may be able to make more accurate UTI diagnoses in this unique population.

In addition to Dr. Pohl, study co-authors include Marcos Pérez-Losada, Ljubica Caldovic, Ph.D., Bruce Sprague and Michael H. Hsieh, M.D., Children’s National; Emma Nally, Suzanne L. Groah and Inger Ljungberg, MedStar National Rehabilitation Hospital; and Neel J. Chandel, Montefiore Medical Center.

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.