Is there a link between RSV and asthma development?

Nusrat Homaira, MBBS, MPH, PhD

Respiratory syncytial virus (RSV) is a frequently battled illness in the youngest patients, but a study shows that while infection frequency might slow as infants age, the lasting effects of the virus may be more significant.

A study published in the Journal of Infectious Diseases reveals that while younger infants become infected most often with RSV to the point of requiring hospitalization, older infants who are hospitalized for RSV may face increased risk of developing asthma and/or chronic wheezing later on in childhood.

"Children who develop severe RSV infection--RSV bronchiolitis in first 12 months of life--are at increased risk of developing subsequent asthma and/or recurrent wheeze, and this risk is higher is children who develop RSV bronchiolitis after 6 months of age," says Nusrat Homaira, MBBS, MPH, PhD, senior lecturer and National Health and Research Council early career fellow in pediatrics at the University of New South Wales in Kensington, Australia, respiratory researcher at Sydney Children's Hospital, and co-author of the report.

Respiratory syncytial virus was responsible for an estimated 3 million hospitalizations in children aged younger than 5 years in 2015 alone, according to the study, with the highest incidence found in children between 6 weeks and 6 months of age. Whereas this illness alone is a burden at this age, there is growing evidence suggesting that severe RSV in a child’s first year of life can increase incidence of asthma or recurrent wheezing developing later in life.

Previous studies have show that children who fall ill with RSV in their first year have a 2- to 4-fold higher risk of developing acute asthma later.

The current study sought to determine if there was an association between the age at which a child experiences their first RSV illness and a later asthma diagnosis. Researchers found that incidence of asthma-associated hospitalization per 1000 child-years among children who were hospitalized for RSV when younger than 3 months of age was 0.5, 0.9 when the child was hospitalized for RSV between 3 and 6 months of age, at 2 when they were hospitalized for RSV between 6 months of age and 1 year, and 1.7 when hospitalization occurred between 1 and 2 years of age. The study authors determined the ratio for hospitalization for asthma was 2- to 7-fold higher in children who were hospitalized for RSV when they were aged 6 months and older, compared to children who were hospitalized for RSV between birth and 6months of age. This means that while more children under 6 months of age fall sick with RSV, the chances of developing asthma subsequently is higher in children who develop RSV infections at 6 months and older.

The study assessed records from children born in New South Wales, Australia, between 2001 and 2010 that had RSV before age 2 years. Out of 888,154 births during that period, 18,402-2%-were hospitalized for RSV in the first 2 years of life. Fifty-seven percent of them were hospitalized for RSV by 6 months of age, and 7.6% of them went on to be hospitalized for asthma beyond age 2 years. Nearly 10% of the children in the cohort had 2 or more hospitalizations for RSV by age 2 years compared with 7.2% who had 1 hospitalization for RSV. Researchers found that children who were hospitalized for RSV by age 2 years had the highest rates of hospitalization for asthma by age 2 years to 3 years, while incidence rates of first hospitalization for asthma beyond age 2 years were not significantly higher than in children who had multiple RSV hospitalizations in the first 2 years of life compared to those with only 1hospitalization.

Overall, the study found that 10% of the children in the cohort who were hospitalized for RSV at 6 months and older also had their first hospitalization for asthma, compared to 6% of children who were hospitalized had their first RSV hospitalization before 6 months of age.

Researchers suggest that the development of asthma after early RSV infection is likely due to both short- and long-term alterations and airway immune response from the airway caused by RSV infection. Younger infants who become sick with RSV may be able to stave off later airway damage and disease development due at least in part to the presence of maternal antibodies, which can last through nearly the first 3 months of life and help protect immature lungs and immune systems. To confirm this theory, the research team notes an observed dose-response relationship between increased risk of hospitalizations for asthma and increasing age at first severe RSV disease, which could be due to waning maternal antibody levels.

"The novel part of the research is that it has shown that while more children get severe RSV infection in the first 6 months of life, the risk of subsequent asthma associated with severe RSV infection is higher in children developing severe RSV infection beyond 6 months of life," Homaira says. "Though this was a first-of-its-kind research and needs to be substantiated with further work, we hypothesize that maternally derived anti-RSV antibody may provide some protection against the extent of airway damage in the first 6 months of life. Also, there is rapid lung alveolar multiplication in the first 6 month of life and it is possible that any lower airway damage due to RSV infection is transient."

Alveolar multiplication and airway remodeling that naturally occurs in the first 6 months of life may also help to stave off permanent airway damage, the report notes. By age 2 to 3 years, lung alveolarization is complete and the RSV disease process is more likely to cause permanent disruption on alveolarization and adverse lung function.

Unfortunately, there is little pediatricians can do to prevent RSV infection, other than to provide basic infection control education to parents and families.

"There are currently no preventive treatment--or screening test--for RSV infection apart from palivizumab, which is only recommended for high-risk children," Homaira says. "However, healthcare providers can promote hand and respiratory hygiene, especially during winter season to limit transmission. Additionally, it’s important for pediatricians to bear in mind that children who are admitted to the hospital in infancy with bronchiolitis can present to them beyond 2 years of age with recurrent wheeze, which may then be diagnosed as asthma."

When asked whether she thought that RSV leads to asthma, or rather that children who have yet to be diagnosed as asthmatic are simply more susceptible to RSV, Homaira says it's a question that can't really be answered just yet.

"This is almost like the 'egg first or the chicken' type question, which is not very easy to prove," Homaira says. "However, there is now a body of work that suggests that early severe RSV infection has a causal association with asthma and that children who develop severe RSV infection can then go on to develop asthma even in absence of atopy or family history of asthma."

Developing an RSV vaccine has been a global health priority, and the report notes that there are currently at least 20 different RSV vaccines in various phases of clinical trials. These vaccines may not only help prevent these dangerous early RSV infections, but also chronic airway diseases that may develop later.

"Currently there are no effective treatment or vaccine against RSV infection in children. However, several vaccines and antibodies are being tested in different phases of clinical trials and the most advanced is a maternal vaccine which will protect infants in the first 6 months of life through placental transfer of enhanced levels of maternal anti-RSV antibody.," Homaira says. "Although children older than 6 months will have a beneficial impact on the long−term consequences of RSV disease as well. We will need several effective RSV vaccines and complementary measures such as monoclonal antibodies to prevent severe RSV disease and chronic respiratory morbidity associated with early severe RSV disease in children."

When effective RSV vaccines become available, passive immunization through maternal vaccination, followed by active immunization in the first 2 years of life, may help in lowering the burden of acute and chronic childhood respiratory diseases associated with RSV.