Oral bacterial lysate to prevent persistent wheeze in infants after severe bronchiolitis; a randomised placebo controlled trial (BLIPA; Bacterial Lysate in Preventing Asthma)

Research question

In infants hospitalised with bronchiolitis, does oral Broncho Vaxom (BV; a lysate of respiratory bacteria), given for 10 days per month for a total of 24 months, prevent parent-reported, doctor-confirmed, wheeze at 18 to 24 months post hospital admission?

The mechanistic question to be addressed is whether BV therapy alters systemic T regulatory and dendritic cells, and increases the diversity of the gut and upper airway microbiota. Background

Bronchiolitis is a common viral infection of the small airways of infants and some affected infants will require hospital admission. Severe bronchiolitis is a marker for greatly increased risk of developing both preschool wheeze and subsequent school age asthma. Since epidemiological studies suggest that exposure to microbial products protects against preschool wheeze, lysates of bacteria may prevent the development of wheeze after bronchiolitis, with long-term beneficial consequences.

Aims and objectives 1) To test whether oral BV prevents parent-reported doctor-confirmed wheeze in infants after severe bronchiolitis.

2) To describe the effect of 24 months of oral BV treatment on markers of systemic T cell and dendritic cell maturation, and on the diversity of the microbiota in the upper airway and gut. Methods

Infants aged 3 to 12 months admitted to hospital with bronchiolitis will be randomly allocated to receive either oral BV 3.5 mg or placebo 10 days a month for 24 months. Trial therapy will be initiated within 4 weeks of hospital discharge. Parents will be contacted every month for presence of wheeze, wheeze therapy, and unscheduled need to medical attention for wheeze. The trial’s primary outcome will be parent-reported and doctor-confirmed wheeze between 18 and 24 months.

A sample size of 894 infants will provide 90% power, with a Type 1 error rate of 5%, and allowing for 13% dropouts, to detect a 40% reduction in active wheeze between 16 and 24 months. This is a recruitment rate of 31%.

The effect of BV on mechanisms for wheeze development will be assessed in the subgroup of infants recruited at the Royal London Hospital. Nasopharyngeal swabs and stool samples for microbiota will be obtained at trial entry and at 24 months, and markers of maturation of systemic T regulatory and dendritic cells, and serum immunoglobulin E, will be assessed at 24 months.

Timelines for delivery

The trial started in January 2021 with regulatory approvals obtained in November 2021. Recruitment of infants will cover 2 winter seasons (2021 and 2022). Data acquisition will end in March 2025 and the trial will end in June 2025. Anticipated impact and dissemination

We will disseminate our results via the peer-reviewed literature and via our extensive links with the media. If the study shows that BV therapy prevents wheeze development, it has the potential to produce significant health benefits. This is because 13% of all cases of asthma in children are associated with previous history of bronchiolitis. If the study is negative, it is of sufficient power to be regarded by the paediatric community to be a definitive result.