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person holding vape and cigarette

E-cigarettes can be a gateway to conventional cigarette smoking

person holding vape and cigarette

A new study finds that e-cigarette use is associated with a higher risk of cigarette smoking among adolescents who had no prior intention of taking up conventional smoking.

Cigarette smoking remains a leading preventable cause of morbidity and mortality in the United States. And while adolescent cigarette smoking has declined over the past several decades, e-cigarette use presents a new risk for nicotine use disorder. A new study, published Nov. 9 in the journal Pediatrics, finds that e-cigarette use is associated with a higher risk of cigarette smoking among adolescents who had no prior intention of taking up conventional smoking. These findings have strong implications for practice and policy, researchers say.

“Research is showing us that adolescent e-cigarette users who progress to cigarette smoking are not simply those who would have ended up smoking cigarettes anyway,” says Olusegun Owotomo, M.D., Ph.D., M.P.H., the study’s lead author and a pediatric resident at Children’s National Hospital. “Our study shows that e-cigarettes can predispose adolescents to cigarette smoking, even when they have no prior intentions to do so.”

In one of the first theory-guided nationally representative studies to identify which adolescent e-cigarette users are at most risk of progressing to cigarette smoking, Researchers looked at data of more than 8,000 U.S. adolescents, ages 12-17, who had never smoked. The data was collected by the Population Assessment of Tobacco and Health (PATH) study, an NIH and FDA collaborative nationally representative prospective cohort study of tobacco use, from 2014-2016. Among adolescents who did not intend to smoke cigarettes in the future, those who used e-cigarettes were more than four times more likely to start smoking cigarettes one year later compared to those who did not use e-cigarettes.

E-cigarette use constitutes a relatively new risk factor for nicotine use disorder among U.S. adolescents. A 2019 study from the Centers for Disease Control and Prevention found that 28% of high school students and 11% of middle school students were current e-cigarette users. With the recent emergence of newer and potentially highly addictive e-cigarette products, adolescents who use e-cigarettes are at increased risk of developing nicotine use disorder and progressing to smoke conventional cigarettes.

“Abstinence from e-cigarettes can protect teens from becoming future smokers and should be framed as a smoking prevention strategy by all concerned stakeholders,” says Dr. Owotomo. “Pediatricians are best positioned to educate patients and families on the clinical and psychosocial consequences of e-cigarette use and should support education campaigns and advocacy efforts geared to discourage adolescent e-cigarette use.”

preterm baby

Validating a better way to stratify BPD risk in vulnerable newborns

preterm baby

Factoring in the total number of days that extremely preterm infants require supplemental oxygen and tracking this metric for weeks longer than usual improves clinicians’ ability to predict respiratory outcomes according to bronchopulmonary dysplasia severity.

Factoring in the total number of days that extremely preterm infants require supplemental oxygen and tracking this metric for weeks longer than usual improves clinicians’ ability to predict respiratory outcomes according to bronchopulmonary dysplasia (BPD) severity, a research team led by Children’s National Hospital writes in Scientific Reports. What’s more, the researchers defined a brand-new category (level IV) for newborns who receive supplemental oxygen more than 120 days as a reliable way to predict which infants are at the highest risk of returning to the hospital due to respiratory distress after discharge.

About 1 in 10 U.S. infants is born preterm, before 37 weeks gestation, according to the Centers for Disease Control and Prevention. That includes extremely preterm infants who weigh about 1 lb. at birth. These very low birthweight newborns have paper thin skin, frail hearts and lungs that are not yet mature enough to deliver oxygen throughout the body as needed. Thanks to advances in neocritical care, an increasing number of them survive prematurity, and many develop BPD, a chronic lung disease characterized by abnormal development of the lungs and pulmonary vasculature.

“About half of the babies born prematurely will come back to the hospital within the first year of life with a respiratory infection. The key is identifying them and, potentially, preventing complications in this high-risk population,” says Gustavo Nino, M.D., a Children’s National pulmonologist and the study’s lead author.

For decades, the most common way to stratify BPD risk in these vulnerable newborns has been to see if they require supplemental oxygen at 36 weeks corrected gestational age.

“The problem with this classification is it doesn’t take into account the very premature babies who are on oxygen for much longer than other babies. So, we asked the question: Can we continue risk stratification beyond 36 weeks in order to identify a subset of babies who are at much higher risk of complications,” Dr. Nino says.

The longitudinal cohort study enrolled 188 infants born extremely preterm who were admitted to the neonatal intensive care unit (NICU) at Children’s National and tracked their data for at least 12 months after discharge. The team used a multidimensional approach that tracked duration of supplemental oxygen during the newborns’ NICU stay as well as scoring lung imaging as an independent marker of BPD severity. To validate the findings, these U.S.-born newborns were matched with 130 infants who were born preterm and hospitalized at two NICUs located in Bogotá, Colombia.

“Babies who are born very preterm and require oxygen beyond 120 days should have expanded ventilation of the lungs and cardiovascular pulmonary system before going home,” he notes. “We need to identify these newborns and optimize their management before they are discharged.”

And, the babies with level IV BPD risk need a different type of evaluation because the complications they experience – including pulmonary hypertension – place them at the highest risk of developing sleep apnea and severe respiratory infection, especially during the first year of life.

“The earlier we identify them, the better their outcome is likely to be,” Dr. Nino says. “We really need to change the risk stratification so we don’t call them all ‘severe’ and treat them the same when there is a subset of newborns who clearly are at a much higher risk for experiencing respiratory complications after hospital discharge.”

In addition to Dr. Nino, Children’s National study co-authors include Awais Mansoor, Ph.D., staff scientist at the Sheikh Zayed Institute for Pediatric Surgical Innovation (SZI); Geovanny F. Perez, M.D., pediatric pulmonologist; Maria Arroyo, M.D., pulmonologist; Xilei Xu Chen, M.D., postdoctoral fellow; Jered Weinstock, pediatric pulmonary fellow; Kyle Salka, MS, research technician; Mariam Said, M.D., neonatologist, and Marius George Linguraru, DPhil, MA, MSc, SZI principal investigator and senior author. Additional co-authors include Ranniery Acuña-Cordero, Universidad Militar Nueva Granada, Bogotá, Colombia; and Monica P. Sossa-Briceño and Carlos E. Rodríguez-Martínez, both of Universidad Nacional de Colombia.

Funding for research described in this post was provided by the National Institutes of Health (NIH) under award Nos. HL145669, AI130502 and HL141237. In addition, the NIH has awarded Dr. Nino an RO1 grant to continue this research.

newborn in incubator

A bronchopulmonary dysplasia primer to guide clinicians and researchers

newborn in incubator

Six months in the writing, the “Bronchopulmonary Dysplasia Primer” published recently by Nature Reviews will be the gold standard review on this topic for years to come.

The term bronchopulmonary dysplasia, or BPD, was first coined in 1967 to describe a chronic lung disease of preterm newborns after treatment with supplemental oxygen via mechanical ventilation in an effort to save their lives. Back then, infants had 50-50 odds of surviving.

In the intervening years, survival has improved and the characteristics of BPD have evolved. Now, BPD is the most common complication of preterm birth for infants born at fewer than 28 weeks’ gestation, as more and more newborns survive premature birth. Hence, the primer.

“The contributing authors are some of the biggest thinkers on this topic,” says Robin H. Steinhorn, M.D., senior vice president, Center for Hospital-Based Specialties, at Children’s National Hospital and author of the section about BPD diagnosis, screening and prevention. “This document will guide clinical education and investigators in the field of BPD. I anticipate this will be the definitive review article on the subject for the next several years.”

Gestational age and low birth weight remain the most potent predictors of BPD. Some 50,000 extremely low gestational age newborns are born each year in the U.S. About 35% will develop some degree of BPD, according to the primer authors.

These newborns are introduced to life outside the womb well before their lungs are ready. Indeed, the pulmonary surfactants needed for normal lung function – a complex mixture of phospholipids that reduce surface tension within the lungs – don’t differentiate until late in pregnancy. Infants who persistently need respiratory support after the 14th day of life are at the highest risk of being diagnosed with BPD at 36 weeks, the coauthors note.

A number of complicating factors can come into play, including maternal diet; fetal exposure to maternal smoking and infection; structural issues such as pre-eclampsia; acute injury from mechanical ventilation and supplemental oxygen; as well as the body’s halting efforts to repair injured, inflamed lung tissue.

“The good news is the number of the smallest and youngest preterm infants who survive extreme preterm birth has steadily increased. Neonatal intensive care units, like our award-winning NICU, now routinely care for babies born at 22 weeks’ gestation,” Dr. Steinhorn says.

Treatment strategies include:

  • Reducing exposure to intubation and ventilation.
  • Leveraging respiratory stimulants, like caffeine.
  • Postnatal steroid therapy.

“Children’s National Hospital is the only center in our immediate region that provides comprehensive care for infants and children with severe BPD,” Dr. Steinhorn adds. “As the population of vulnerable and fragile infants has grown, we have invested in the equipment and the personnel – including at the Hospital for Sick Children Pediatric Center (HSC) – to create a very safe and supportive environment that improves survival and quality of life.”

Some preterm infants spend their first 9 to 10 months of life at Children’s National, and their days are filled with concentrated physical, occupational and speech therapy, as well as music and play therapy to hasten their rehabilitation.

Once their medical condition stabilizes, they transition to HSC to focus more intently on rehabilitation.

“We see HSC as filling a very important role in their care. When our children graduate to HSC, they are going for ongoing care of their lung disease, but also their ongoing rehabilitation. At HSC, they focus on creating the most normal life that we can possibly create and, over time, that is a life free of ventilators and tracheostomy tubes.”

In addition to Dr. Steinhorn, BPD Primer co-authors include Bernard Thébaud, Children’s Hospital of Eastern Ontario; Kara N. Goss, University of Wisconsin-Madison; Matthew Laughon, The University of North Carolina at Chapel Hill; Jeffrey A. Whitsett and Alan H. Jobe, Cincinnati Children’s Hospital Medical Center; Steven H. Abman, Children’s Hospital Colorado;  Judy L. Aschner, Joseph M. Sanzari Children’s Hospital; Peter G. Davis, The Royal Women’s Hospital; Sharon A. McGrath- Morrow, Johns Hopkins University School of Medicine; and Roger F. Soll, University of Vermont.

Financial support for the research described in this post was provided by the National Institutes of Health under grant Nos. U01HL122642, U01HL134745, RO1HL68702, R01HL145679, U01HL12118-01 and K24 HL143283; the Australian National Health and Medical Research Council; the Canadian Institute for Health Research; Stem Cell Network and the Ontario Institute for Regenerative Medicine.

electronic cigarette dispenser with different flavors of nicotine

Extreme difficulty breathing and swallowing linked to teen’s vaping?

electronic cigarette dispenser with different flavors of nicotine

After a teen was transferred to Children’s National Hospital suffering from severe difficulty breathing and swallowing, a multidisciplinary team continued the detective work and surmises that vaping was to blame for her unusual symptoms.

A teenage girl with no hint of prior asthma or respiratory illness began to feel hoarseness in her throat and a feeling that she needed to clear her throat frequently. Within a few weeks, her hoarseness and throat-clearing worsened with early morning voice loss and feeling as if food were lodged in her throat. She started having trouble swallowing and began to avoid food all together.

Her pediatrician prescribed loratadine for suspected allergies to no avail. Days later, an urgent care center prescribed a three-day course of prednisone. For a few days, she felt a little better, but went back to feeling like she was breathing “through a straw.” After going to an emergency room with acute respiratory distress and severe difficulty swallowing, staff tried intravenous dexamethasone, ampicillin/sulbactam, and inhaled racemic epinephrine and arranged for transfer.

When she arrived at Children’s National Hospital, a multidisciplinary team continued the detective work with additional testing, imaging and bloodwork.

Examining her throat confirmed moderate swelling and a partially obstructed airway draped with thick chartreuse-colored mucus. The teen had no history of an autoimmune disorder, no international travel and no exposure to animals. She had no fever and had received all her scheduled immunizations.

“With epiglottitis – an inflammation of the flap found at the base of the tongue that prevents food from entering the trachea – our first concern is that an underlying infection is to blame,” says Michael Jason Bozzella, D.O., MS, a third-year infectious diseases fellow and lead author of the case report published Feb. 5, 2020, in Pediatrics. “We tested her specimens in a number of ways for a host of respiratory pathogens, including human rhino/enterovirus, respiratory syncytial virus, influenza, Epstein-Barr virus, Streptococcus and more. All negative. We also looked for more atypical infections with bacteria, like Arcanobacterium, Mycoplasma and Gonorrhea. Those were all negative as well,” Dr. Bozzella adds.

She slowly improved during a seven-day initial hospital stay, though soon returned for another six-day hospital stay after it again became excruciatingly painful for her to swallow.

Every throat culture and biopsy result showed no evidence of fungal, bacterial or viral infection, acid-fast bacilli or other malignancy. But in speaking with doctors, the teen had admitted to using candy-and fruit-flavored e-cigarettes three to five times with her friends over the two months preceding her symptoms. The last time she vaped was two weeks before her unusual symptoms began.

According to the Centers for Disease Control and Prevention, 2,668 people in the U.S. have been hospitalized for e-cigarette or vaping product use-associated lung injury, as of Jan. 14, 2020. The Children’s National case report’s authors say the increasing use of vaping products by teenagers highlights the potential for unknown health risks to continue to grow.

“This teenager’s use of e-cigarettes is the most plausible reason for this subacute epiglottitis diagnosis, a condition that can become life-threatening,” says Kathleen Ferrer, M.D., a hospitalist at Children’s National and the case report’s senior author. “This unusual case adds to a growing list of toxic effects attributable to vaping. While we normally investigate infectious triggers, like Streptococci, Staphylococci and Haemophilus, we and other health care providers should also consider e-cigarettes as we evaluate oro-respiratory complaints.”

In addition to Drs. Bozzella and Ferrer, Children’s National case report co-authors include Matthew Allen Magyar, M.D., a hospitalist; and Roberta L. DeBiasi, M.D., MS, chief of the Division of Pediatric Infectious Diseases.

little boy using asthma inhaler

Searching for the molecular underpinnings of asthma exacerbations

little boy using asthma inhaler

It’s long been known that colds, flu and other respiratory illnesses are major triggers for asthma exacerbations, says asthma expert Stephen J. Teach, M.D., MPH. Consequently, a significant body of research has focused on trying to figure out what’s happening on the cellular or molecular level as these illnesses progress to exacerbations.

People with asthma can be indistinguishable from people who don’t have this chronic airway disease – until they have an asthma attack, also known as an exacerbation. During these events, their airways become inflamed and swollen and produce an abundance of mucus, causing dangerous narrowing of the bronchial tubes that leads to coughing, wheezing and trouble breathing. These events are a major cause of morbidity and mortality, leading to the deaths of 10 U.S. residents every day, according to the Centers for Disease Control and Prevention.

It’s long been known that colds, flu and other respiratory illnesses are major triggers for asthma exacerbations, says Children’s National in Washington, D.C., asthma expert Stephen J. Teach, M.D., MPH. Consequently, a significant body of research has focused on trying to figure out what’s happening on the cellular or molecular level as these illnesses progress to exacerbations. Targeted searches have identified several different molecular pathways that appear to be key players in this phenomenon. However, Dr. Teach says researchers have been missing a complete and unbiased snapshot of all the important pathways in illness-triggered exacerbations and how they interrelate.

To develop this big picture view, Dr. Teach and  Inner-City Asthma Consortium colleagues recruited 208 children ages 6-17 years old with severe asthma – marked by the need for daily doses of inhaled corticosteroids, two hospitalizations or systemic corticosteroid treatments over the past year, and a high concentration of asthma-associated immune cells – from nine pediatric medical centers across the country, including Children’s National. (Inhaled corticosteroids are a class of medicine that calms inflamed airways.) The researchers collected samples of nasal secretions and blood from these patients at baseline, when all of them were healthy.

Then, they waited for these children to show symptoms of respiratory illnesses. Within six days of cold symptoms, the researchers took two more samples of nasal secretions and blood. They also administered breathing tests to determine whether these respiratory illnesses led to asthma exacerbations and recorded whether these patients were treated with systemic corticosteroids to stem the associated respiratory inflammation.

The researchers examined nasal fluid samples for evidence of viral infection during illness and used analytical methods to identify the causative virus. They analyzed all the samples they collected for changes in concentrations of various immune cells. They also looked globally in these samples for changes in gene expression compared with baseline and between the two collection periods during respiratory illness.

Together, this information told the molecular story about what took place after these children got sick and after some of them developed exacerbations. Of the 208 patients recruited, 106 got respiratory illnesses during the six-month study period, leading to a total of 154 illness events. Of those, 47 caused exacerbations, and 107 didn’t.

About half the exacerbations appeared to have been triggered by a rhinovirus, a cause of common colds, the research team reports in a study published online April 8, 2019, in Nature Immunology. The other children’s cold-like symptoms could have been triggered by pollution, allergens or other irritants.

In most exacerbations, virally triggered or not, the researchers saw early activation of a network of genes that appeared to be associated with SMAD3, a signaling molecule already known to be involved in airway inflammation. At the same time, genes that control a set of immune cells known as lymphocytes were turned down. However, as the exacerbation progressed and worsened, the researchers saw gene networks turned on that related to airway narrowing, mucus hypersecretion and activation of other immune cells.

Exacerbations triggered by viruses were associated with multiple inflammatory pathways, in contrast to those in which viruses weren’t found, which were associated with molecular pathways that affected cells in the airway lining.

The researchers validated these findings in 19 patients who each got respiratory illnesses at least twice during the study period but only developed an exacerbation during one of these episodes, finding the same upregulated and downregulated molecular pathways in these patients as in the study population as a whole. They also identified a set of molecular risk factors in patients at baseline – signatures of gene activation that appeared to put patients at risk for exacerbations when they got sick. When patients were treated with systemic corticosteroids during exacerbations, these medicines appeared to restore only some of the affected molecular pathways to normal, healthy levels. Other molecular pathways remained markedly changed.

Each finding could represent a new target for drugs that could prevent or more effectively treat exacerbations, keeping more patients with asthma healthy and out of the hospital.

“Our consortium study found increased gene expression of enzymes that produce molecules that contribute to narrowed airways and dilated blood vessels,” Dr. Teach adds. “This is especially intriguing because drugs that target kallikreins or bradykinin may help treat asthma attacks that aren’t caused by viruses.”

In addition to Dr. Teach, study co-authors include Lead Author Matthew C. Altman, University of Washington; Michelle A. Gill, Baomei Shao and Rebecca S. Gruchalla, all of University of Texas Southwestern Medical Center; Elizabeth Whalen and Scott Presnell of Benaroya Research Institute; Denise C. Babineau and Brett Jepson of Rho, Inc.; Andrew H. Liu, Children’s Hospital Colorado; George T. O’Connor, Boston University School of Medicine; Jacqueline A. Pongracic, Ann Robert H. Lurie Children’s Hospital of Chicago; Carolyn M. Kercsmar and Gurjit K. Khurana Hershey, , Cincinnati Children’s Hospital; Edward M. Zoratti and Christine C. Johnson, Henry Ford Health System; Meyer Kattan, Columbia University College of Physicians and Surgeons; Leonard B. Bacharier and Avraham Beigelman, Washington University, St. Louis; Steve M. Sigelman, Peter J. Gergen, Lisa M. Wheatley and Alkis Togias, National Institute of Allergy and Infectious Diseases; and James E. Gern, William W. Busse and Senior author Daniel J. Jackson, University of Wisconsin School of Medicine and Public Health.

Funding for research described in this post was provided by the National Institute of Allergy and Infectious Diseases under award numbers 1UM1AI114271 and UM2AI117870; CTSA under award numbers UL1TR000150, UL1TR001422 and 5UL1TR001425; the National Institutes of Health under award number UL1TR000451;  CTSI under award number 1UL1TR001430; CCTSI under award numbers UL1TR001082 and 5UM1AI114271; and NCATS under award numbers UL1 TR001876 and UL1TR002345.

dystrophin protein

Experimental drug shows promise for slowing cardiac disease and inflammation

dystrophin protein

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, which provides instructions for making dystrophin, a protein found mostly in skeletal, respiratory and heart muscles.

Vamorolone, an experimental medicine under development, appears to combine the beneficial effects of prednisone and eplerenone – standard treatments for Duchenne muscular dystrophy (DMD) – in the heart and muscles, while also showing improved safety in experimental models. The drug does so by simultaneously targeting two nuclear receptors important in regulating inflammation and cardiomyopathy, indicates a small study published online Feb. 11, 2019, in Life Science Alliance.

DMD is a progressive X-linked disease that occurs mostly in males. It is characterized by muscle weakness that worsens over time, and most kids with DMD will use wheelchairs by the time they’re teenagers. DMD is caused by mutations in the DMD gene, which provides instructions for making dystrophin, a protein found mostly in skeletal, respiratory and heart muscles.

Cardiomyopathy, an umbrella term for diseases that weaken the heart, is a leading cause of death for young adults with DMD, causing up to 50 percent of deaths in patients who lack dystrophin. A collaborative research team co-led by Christopher R. Heier, Ph.D., and Christopher F. Spurney, M.D., of Children’s National Health System, is investigating cardiomyopathy in DMD. They find genetic dystrophin loss provides “a second hit” for a specific pathway that worsens cardiomyopathy in experimental models of DMD.

“Some drugs can interact with both the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) since these two drug targets evolved from a common ancestor. However, we find these two drug targets can play distinctly different roles in heart and skeletal muscle. The GR regulates muscle inflammation, while the MR plays a key role in heart health,” says Heier, an assistant professor at Children’s National and lead study author. “In our study, the experimental drug vamorolone safely targets both the GR to treat chronic inflammation and the MR to treat the heart.”

After gauging the efficacy of various treatments in test tubes, the study team looked at whether any could mitigate negative impacts of the MR on heart health. Wild type and mdx experimental models were implanted with pumps that activated the MR. These models also received a daily oral MR antagonist (or inhibitor) drug, and either eplerenone, spironolactone or vamorolone. Of note:

  • MR activation increased kidney size and caused elevated blood pressure (hypertension).
  • Treatment with vamorolone maintained normal kidney size and prevented hypertension.
  • MR activation increased mdx heart mass and fibrosis. Vamorolone mitigated these changes.
  • MR activation decreased mdx heart function, while vamorolone prevented declines in function.
  • Daily prednisone caused negative MR- and GR-mediated side effects, such as hyperinsulinemia, whereas vamorolone safely improved heart function without these side effects.

“These findings have the potential to help current and future patients,” Heier says. “Clinicians already prescribe several of these drugs. Our new data support the use of MR antagonists such as eplerenone in protecting DMD hearts, particularly if patients take prednisone. The experimental drug vamorolone is currently in Phase IIb clinical trials and is particularly exciting for its unique potential to simultaneously treat chronic inflammation and heart pathology with improved safety.”

In addition to Heier and senior author Spurney, study co-authors include Qing Yu, Alyson A. Fiorillo, Christopher B. Tully, Asya Tucker and Davi A. Mazala, all of Children’s National; Kitipong Uaesoontrachoon and Sadish Srinivassane, AGADA Biosciences Inc.; and Jesse M. Damsker, Eric P. Hoffman and Kanneboyina Nagaraju, ReveraGen BioPharma.

Financial support for research described in this report was provided by Action Duchenne; the Clark Charitable Foundation; the Department of Defense under award W81XWH-17-1-047; the Foundation to Eradicate Duchenne; the Intellectual and Developmental Disabilities Research Center under award U54HD090257 (through the National Institutes of Health’s (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development); and the NIH under awards K99HL130035, R00HL130035, L40AR068727 and T32AR056993.

Financial disclosure:  Co-authors employed by ReveraGen BioPharma were involved in creating this news release.