Azithromycin does not prevent future wheezing in babies with RSV infection

New research of azithromycin suggests the antibiotic does not prevent wheezing in babies hospitalised with RSV infection.

Respiratory syncytial virus (RSV) infection is a common virus and almost all children are infected with it by two years old. In older children and adults, RSV infection can cause a cough or cold, but in young children, it can cause bronchiolitis.

The antibiotic azithromycin has anti-inflammatory properties that can be beneficial in some chronic lung diseases, such as cystic fibrosis. The researchers investigated this antibiotic’s potential to prevent future recurrent wheezing amongst infants hospitalised with RSV infection. As, after an RSV infection, babies are at risk of developing asthma later in childhood, the scientists hoped to find a therapy to reduce this risk.

The results of the study were presented at the annual meeting of the American Academy of Allergy, Asthma & Immunology in Phoenix and published in The New England Journal of Medicine – Evidence. The new study was led by researchers at Washington University School of Medicine in St. Louis and Vanderbilt University.

Studying RSV infection

In infants and young children, RSV infection can cause bronchiolitis, an infection of the small airways in the lungs. Nearly all children contract RSV infections at some point in early childhood, and a small percentage develop bronchiolitis severe enough to be hospitalised. Infants hospitalised with RSV bronchiolitis are at an increased risk of developing asthma.

With parental permission, the researchers randomly assigned 200 infants, that were hospitalised at St. Louis Children’s Hospital for RSV bronchiolitis, to receive oral azithromycin or a placebo for two weeks.

The babies were healthy, other than RSV infection, and ranged in age from one month to 18 months. Additionally, the researchers received approval from the Food and Drug Administration (FDA) to give infants azithromycin—a commonly prescribed antibiotic used in children aged two and older— as part of this clinical trial.

The patients were enrolled during three consecutive RSV infection seasons, from 2016 to 2019, and were followed for two to four years after hospitalisation. The researchers kept track of whether the infants received any other antibiotics before or during their hospital stays. For example, a child’s paediatrician could choose to prescribe other antibiotics if the child also developed an ear infection or was suspected of developing bacterial pneumonia or another bacterial infection. Amoxicillin was the most common additional antibiotic prescribed.

The findings

Within the infants hospitalised with RSV infection, the researchers found no difference in the amount of wheezing in babies treated with azithromycin versus those who received a placebo. Furthermore, the difference in the amount of wheezing did not reach statistical significance.

“About half of infants admitted to a hospital with RSV will be diagnosed with asthma by age seven,” said first author Avraham Beigelman, MD, an associate professor of paediatrics and a paediatric allergist and immunologist in the Division of Allergy & Pulmonary Medicine in the Department of Paediatrics at Washington University School of Medicine. “We are interested in finding approaches to prevent the development of asthma after RSV infection.

“Azithromycin has anti-inflammatory effects in other airway diseases, such as cystic fibrosis. We also had data in mice and data from a smaller clinical trial of hospitalised infants that suggested azithromycin reduced wheezing following RSV infection. So, we were surprised by the negative results of this larger trial.”

The current trial illuminated that azithromycin lowers a marker of airway inflammation called IL-8; infants treated with azithromycin had lower levels of IL-8 in their noses than infants who received a placebo, thus confirming the anti-inflammatory effects of azithromycin.

Even with this discovery, azithromycin-treated patients did not have a reduced risk of developing recurrent wheezing following RSV infection compared with the placebo group, and while the difference did not reach statistical significance, the data appeared to favour that this antibiotic treatment increased the risk of wheezing.

This is observed by the 47% of patients who had received azithromycin experiencing recurrent wheezing versus 36% of the placebo group. Recurrent wheezing was defined as three episodes of wheezing during the two to four years follow up.

“There may be an increase in the risk of recurrent wheezing with any antibiotic use,” Beigelman said. “We want to be cautious in our interpretation of this potentially negative effect of antibiotics, as the study was not designed to test the effects of different antibiotics.

“However, this is an important message to be communicated to paediatricians, since antibiotics are frequently given to patients with RSV bronchiolitis despite the fact that this practice is not supported by clinical guidelines. At the very least, azithromycin and antibiotics in general have no benefit in preventing recurrent wheeze, and there is a possibility they are harmful.”

Beigelman concluded the researchers also collected airway microbiome samples from these patients and plan to investigate whether bacteria colonising the airway may interact with the antibiotics and have an impact on wheezing. Researchers also plan to analyse stool samples collected from the same infants to see whether the gut microbiome may have a role in wheezing and the subsequent risk of developing asthma in childhood.


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