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Link between early lower respiratory tract infections and obstructive sleep apnea

smiling baby sleeping

For the first time, researchers at Children’s National Hospital have identified the association between early LRTI and the development of OSA in children.

Several birth cohorts have defined the pivotal role of early lower respiratory tract infections (LRTI) in the inception of pediatric respiratory conditions. However, the association between early LRTI and the development of obstructive sleep apnea (OSA) in children had not previously been made.

Now, for the first time, researchers at Children’s National Hospital have identified the association between early LRTI and the development of OSA in children, according to a study published in the journal SLEEP.

“These results suggest that respiratory syncytial virus LRTI may contribute to the pathophysiology of OSA in children,” said Gustavo Nino, M.D., director of sleep medicine at Children’s National.

The study also demonstrated that children with a history of severe respiratory syncytial virus (RSV) bronchiolitis during early infancy had more than double the odds of developing OSA during the first five years of life independently of other risk factors.

“The results suggest that RSV LRTI may contribute to the pathophysiology of OSA in children, raising concern for the possibility that primary prevention strategies can hinder the initial establishment of OSA following early viral LRTIs,” said Dr. Nino. “Primary prevention of OSA in children would have a dramatic effect in reducing the increasing incidence of this condition and in preventing its detrimental effects on childhood health and beyond.”

The novel findings also raise the possibility that anticipatory strategies and interventions can be developed to identify and prevent the initial establishment of OSA following viral respiratory infections during early infancy. This could provide a dramatic effect in reducing the increasing incidence of this condition and its multiple detrimental effects on childhood health and beyond.

“Our study offers a new paradigm for investigating mechanisms implicated in the early pathogenesis of OSA in the pediatric population,” said Dr. Nino.

Marishka Brown, Ph.D., director of the National Center on Sleep Disorders Research at the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health (NIH), agreed.

“The findings from this study suggest that viral lower respiratory tract infections could predispose to the development of sleep-disordered breathing in later childhood,” Brown said. “More research to determine how these infections affect airway function could lead to a better understanding of how sleep apnea develops in pediatric patients.”

This study includes funding support from the NIH, including the NHLBI.

The Pulmonary Division at Children’s National has been ranked as one of the top ten programs in the nation by U.S. News & World Report.

illustration of lungs with virus

Segmenting viral bronchiolitis patients to better predict clinical outcomes

illustration of lungs with virus

By evaluating viral bronchiolitis patients at first presentation and categorizing them based on clinical phenotype, the researchers were able to better predict outcomes and disease progression patterns.

Researchers from Children’s National Hospital have recently published a pilot study of children with viral bronchiolitis. By evaluating viral bronchiolitis patients at first presentation and categorizing them based on clinical phenotype, the researchers were able to better predict outcomes and disease progression patterns. Nasal airway cytokine levels were also measured to assess the underlying airway immunobiology of different clinical phenotypes. The researchers believe this novel subdivision of viral bronchiolitis patients based on a robust combination of clinical and molecular assessment can help lead to more individualized care and better patient outcomes.

Viral bronchiolitis is broadly used to group together infants with first-time severe viral respiratory infection, which is the most common cause of early life sick visits and hospitalizations worldwide. However, viral respiratory infections can vary significantly in clinical manifestations, which has raised concern among experts that the use of viral bronchiolitis as a catchall term may be compromising patient care. Children’s National researchers hypothesized that a novel segmentation technique of viral bronchiolitis patients by phenotype at first episode could provide better outcome prediction. In addition, lung X-rays and nasal cytokine profiles could help illuminate the underlying airway disease processes that drive the phenotypical differences observed at bedside.

The study examined 50 children ≤ 2 years old, including 41 patients admitted at Children’s National with PCR-confirmed viral respiratory infection and 9 controls. Researchers examined clinical features at presentation by reviewing each patient’s electronic medical record. Key parameters served as the basis for patient segmentation into three phenotypical groups: hypoxemia, wheezing and mild phenotypes. Patients in the hypoxia group (n = 16) were characterized by their need for supplemental oxygen; patients in the wheezing phenotype (n = 16) were distinguished by wheezing or subcostal retractions and patients in the mild phenotype (n = 9) displayed persistent respiratory symptoms but not hypoxia, wheezing or subcostal retractions. Chest x-rays further revealed that patients in the hypoxia phenotype displayed significantly more lung opacities than the other phenotypes.

As hypothesized, the three phenotype groups displayed distinct clinically relevant outcomes. Patients in the hypoxia group had more severe clinical symptoms at presentation and were significantly more likely to require prolonged hospitalization and pediatric intensive care unit (PICU) settings for treatment. Patients in the wheezing phenotype had shorter hospital stays but were significantly more likely to make a respiratory sick visit after initial discharge, with 69% coming back to the hospital with the same symptoms. Patients in the mild phenotype had the shortest hospital stays and did not require transfer to the PICU.

Nasal cytokine profiles were also assessed for all study subjects. Controls had lower cytokine levels than patients, with no significant difference between phenotype groups. However, wheezing patients with ≥1 recurrent respiratory sick visit had higher nasal levels of type 2 cytokines IL-13 and IL-4, consistent with the pathobiology of allergic asthma. This result adds support for the potential of initial sub-setting in guiding timely intervention.

The researchers hope that the strong results of their pilot study will guide clinicians to revise current practices regarding viral bronchiolitis and personalize care of viral respiratory illnesses from first presentation in order to improve outcomes. Study author and Children’s National pulmonologist Maria Arroyo, M.D., says, “if we can prevent these patients from coming [back] to the hospital just by doing a clinical evaluation the first time that they present with [viral respiratory infection]…that would be very impactful.”

The associated article, “Phenotypical Sub-setting of the First Episode of Severe Viral Respiratory Infection Based on Clinical Assessment and Underlying Airway Disease: A Pilot Study,” was published April 2, 2020 in Frontiers in Pediatrics. Notable authors include Maria Arroyo, M.D., Kyle Salka, M.S., and Gustavo Nino, M.D., M.S.H.S., D.A.B.S.M.

Human Rhinovirus

Finding the root cause of bronchiolitis symptoms

Human Rhinovirus

A new study shows that steroids might work for rhinovirus but not for respiratory syncytial virus.

Every winter, doctors’ offices and hospital emergency rooms fill with children who have bronchiolitis, an inflammation of the small airways in the lung. It’s responsible for about 130,000 admissions each year. Sometimes these young patients have symptoms reminiscent of a bad cold with a fever, cough and runny nose. Other times, bronchiolitis causes breathing troubles so severe that these children end up in the intensive care unit.

“The reality is that we don’t have anything to treat these patients aside from supportive care, such as intravenous fluids or respiratory support,” says Robert J. Freishtat, M.D., M.P.H., chief of emergency medicine at Children’s National Health System. “That’s really unacceptable because some kids get very, very sick.”

Several years ago, Dr. Freishtat says a clinical trial tested using steroids as a potential treatment for bronchiolitis. The thinking was that these drugs might reduce the inflammation that’s a hallmark of this condition. However, he says, the results weren’t a slam-dunk for steroids: The drugs didn’t seem to improve outcomes any better than a placebo.

But the trial had a critical flaw, he explains. Rather than having one homogenous cause, bronchiolitis is an umbrella term for a set of symptoms that can be caused by a number of different viruses. The most common ones are respiratory syncytial virus (RSV) and rhinovirus, the latter itself being an assortment of more than 100 different but related viruses. By treating bronchiolitis as a single disease, Dr. Freishtat says researchers might be ignoring the subtleties of each virus that influence whether a particular medication is useful.

“By treating all bronchiolitis patients with a single agent, we could be comparing apples with oranges,” he says. “The treatment may be completely different depending on the underlying cause.”

To test this idea, Dr. Freishtat and colleagues examined nasal secretions from 32 infants who had been hospitalized with bronchiolitis from 2011 to 2014 at 17 medical centers across the country that participate in a consortium called the 35th Multicenter Airway Research Collaboration. In half of these patients, lab tests confirmed that their bronchiolitis was caused by RSV; in the other half, the cause was rhinovirus.

From these nasal secretions, the researchers extracted nucleic acids called microRNAs. These molecules regulate the effects of different genes through a variety of different mechanisms, usually resulting in the effects of target genes being silenced. A single microRNA typically targets multiple genes by affecting messenger RNA, a molecule that’s key for producing proteins.

Comparing results between patients with RSV or rhinovirus, the researchers found 386 microRNAs that differed in concentration. Using bioinformatic software, they traced these microRNAs to thousands of messenger RNAs, looking for any interesting clues to important mechanisms of illness that might vary between the two viruses.

Their findings eventually turned up important differences between the two viruses in the NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway, a protein cascade that’s intimately involved in the inflammatory response and is a target for many types of steroids. Rhinovirus appears to upregulate the expression of many members of this protein family, driving cells to make more of them, and downregulate inhibitors of this cascade. On the other hand, RSV didn’t seem to have much of an effect on this critical pathway.

To see if these effects translated into cells making more inflammatory molecules in this pathway, the researchers searched for various members of this protein cascade in the nasal secretions. They found an increase in two, known as RelA and NFkB2.

Based on these findings, published online Jan. 17, 2018, in Pediatric Research, steroids might work for rhinovirus but not for RSV, notes Dr. Freishtat the study’s senior author.

“We’re pretty close to saying that you’d need to conduct a clinical trial with respect to the virus, rather than the symptoms, to measure any effect from a given drug,” he says.

Future clinical trials might test the arsenal of currently available medicines to see if any has an effect on bronchiolitis caused by either of these two viruses. Further research into the mechanisms of each type of illness also might turn up new targets that researchers could develop new medicines to hit.

“Instead of determining the disease based on symptoms,” he says, “we can eventually treat the root cause.”

Study co-authors include Kohei Hasegawa, study lead author, and Carlos A. Camargo Jr., Massachusetts General Hospital; Marcos Pérez-Losada, The George Washington University School of Medicine and Health Sciences; Claire E. Hoptay, Samuel Epstein and Stephen J. Teach, M.D., M.P.H., Children’s National; Jonathan M. Mansbach, Boston Children’s Hospital; and Pedro A. Piedra, Baylor College of Medicine.