Infants who develop a “wheezing illness” or have been infected by respiratory syncytial virus (RSV) before their 1st birthday are at increased risk for subsequent and severe viral infections and childhood asthma, according to researchers at Vanderbilt University Medical Center and Northwestern University.
Their findings, reported May 23 in the journal Science Advances, suggest a possible way to identify susceptibility to — and prevent the development of — asthma and other severe respiratory problems later in life.
“This study is critical for identifying how wheezing illnesses and early-life RSV infections modify the ability for airway epithelial cells to develop and provide an effective barrier against respiratory viruses and bacteria,” said Dawn Newcomb, PhD, associate professor of Medicine and Pathology, Microbiology and Immunology at VUMC.
“Our findings provide a reason, among many, for how wheezing and early-life RSV increase the risk of childhood asthma,” she said.
Newcomb and Sergejs Berdnikovs, PhD, currently at the University of Colorado Anschutz Medical Campus in Aurora, are the paper’s co-first authors. They led the project with senior author Tina Hartert, MD, MPH, the Lulu H. Owen Professor of Medicine and director of the Center for Asthma Research at VUMC.
“The airway is abnormal in asthma,” Hartert explained. “Understanding how the airway develops normally and in conditions like asthma is critical to understanding the disease and developing biologically targeted ways to prevent and treat asthma.”
Asthma is the most common chronic childhood disease, and the incidence is rising. Most asthma arises before the age of 6, and there is no cure for it, although it can be managed with medications and by avoiding individual asthma triggers, such as pollen, dust and tobacco smoke.
Genetic factors also are involved in asthma, as are viral infections that impair breathing.
An important asthma trigger is RSV, which each year is responsible for the hospitalizations of more than 50,000 children under age 5, according to the Centers for Disease Control and Prevention.
To better understand the origins of asthma, Hartert and her colleagues recruited and have continued to follow a birth cohort of nearly 2,000 children born in Middle Tennessee between 2012-2014.
Supported by the National Institutes of Health, the Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure (INSPIRE) cohort has yielded important insights into the relationship between RSV infection during infancy, and the development of wheezing and asthma later in life.
The latest study examined nasal airway epithelial cells swabbed from the noses of children in the INSPIRE cohort when they were 2- to 3-years-old. The nasal airway epithelium, which continues to develop after birth, is a mucosal barrier and a first line of defense against viral infections and other illnesses and parallels what occurs in the lung in asthma.
The researchers were surprised to discover that the development of nasal airway epithelial cells collected from children with wheezing illness and grown in culture were altered in ways that increased the permeability of the epithelial barrier and blunted the antiviral immune response.
The most marked changes in the airway were observed in children who developed a wheezing illness and who also were infected by RSV in the first year of life.
“Findings from this study indicate that children who develop wheezing have different airway characteristics early in life, even before they develop asthma,” Hartert said. “Infections like RSV during the first year further change how their airways develop.”
“These findings provide insights into what parts of asthma may be hereditary or develop during pregnancy, and which key developmental pathways are altered by preventable early life exposures,” she said.
In conclusion, the researchers suggested that a potential “gene-by-environment interaction” may contribute to and explain the association of early-life RSV infection with childhood asthma risk.
“Identifying the timing and pathways driving epithelial development may inform additional targets for prevention and treatment approaches,” they wrote.
In addition to researchers from Northwestern, co-authors from VUMC included Kaitlin McKernan, Shelby Kuehnle and Jacqueline-Yvonne Cephus, MS, from the Newcomb lab, Tebeb Gebretsadik, MPH, senior associate in Biostatistics, Siyuan Ma, PhD, assistant professor of Biostatistics, and Christian Rosas-Salazar, MD, PhD, assistant professor of Pediatrics.
The research was supported in part by NIH grants U19AI095227, K24AI077930, UG3OD023282 and UL1TR000445, the Vanderbilt Institute for Clinical and Translational Research, the Children’s Allergy and Asthma Data Repository program, and the Vanderbilt Center for Asthma Research.
