The immune milieu of bronchiolitis and impact of bacterial lysates

Background:

Overall, 33% of all UK infants will develop clinical bronchiolitis, and 3% of all UK infants will require admission to hospital for this disease . The long-term consequences of severe bronchiolitis have been extensively reported with consistent evidence that infants admitted to hospital with bronchiolitis are at greatly increased risk of subsequent asthma. First, Dumas et al, in a study of infants admitted to hospital with bronchiolitis, found that by 3 years of age, 27% had developed recurrent episodes of wheeze requiring doctor-prescribed therapy (1). Second, Valkonen et al reported that 3 years after hospital admission for infant bronchiolitis, 23% of children were being prescribed asthma medications (2). Third, Bacharier et al followed up infants with bronchiolitis for up to 6 years and found that by 24 months of age 35% of infants who had severe bronchiolitis had developed doctor-diagnosed preschool wheeze or asthma (personal communication), and that by 7 years of age 47% had doctor-diagnosed active school-age asthma(3).

While is it unlikely that this single infection causes asthma on its own, it is likely that an immaturity in immune development may in conjunction with external factors such as air pollution exposure result in predisposition to asthma which is then triggered by the specific infection in childhood.

To date the mechanisms underlying this potential predisposition are unclear, but could in part be explained by;

1. T cells; a reduced frequency of activated regulatory T cells (aTregs) are reported in the blood of RSV-infected infants compared with healthy age-matched controls (4).
2. Cytokines; reduced levels of interleukin (IL)-33, a cytokine required for Treg maintenance within mucosal tissues, is reported in nasal wash samples (4).
3. microbiota; an increased proportion of Haemophilus-dominant nasopharyngeal microbiota profiles during bronchiolitis is associated with an increased risk of active wheeze/asthma at 3 years(5).
4. dendritic cells (DCs); in an animal model of bronchiolitis, depletion of plasmacytoid (p) DCs during viral bronchiolitis is associated with failure to expand Tregs, an increased severity of bronchiolitis, and an increased severity of a subsequent asthma-like disease(5).

It has been proposed that bacterial lysates (Bronchovaxom, BV) may act on these pathways to reduce the risk of developing wheezing illnesses.

Although clinical studies suggest an effect of BV on children’s innate immunity, specific mechanisms of action have not been elucidated. However, animal models suggest that oral BV treatment modulates T and dendritic cell function in the airway.

Hypothesis

Exposure of infants to a key sentinel bronchiolitis infection in infancy impacts the immune milieu of the upper airway and blood, increasing the risk of developing recurrent wheeze in the preschool period.

AIMS

·      Identify the immune cell phenotype of infants with bronchiolitis and healthy infants

·      Assess the impact of early viral infections on the cells found in the nose

·      Assess the impact of a bacterial lysate on the immune cell phenotype

Study Methodology and Design:

To test this hypothesis 100 infants with bronchiolitis and age matched controls (50 of each) will be recruited between the ages of 3 and 12 months. They will have initial baseline collection of nasal cells and blood samples alongside clinical and medical history including birth history. They will then be followed up for 24 months to assess for the development of wheezing illnesses. This will be assessed through a regular diary and parental reporting of wheeze episodes. 

To assess biomarkers of the impact of bronchiolitis on the immune cell phenotype vulnerability to air pollution, blood samples will be explored for dendritic and t-cell phenotype alongside an assessment of t-cell function, alongside expression of cytokines. Nasal samples will be assessed for mucosal inflammatory responses using multiplex assays. Nasal cells will be obtained through non-painful nasopharyngeal aspirate collection. 

As an experimental addition this study will utilise an innovative wheeze listening device as part of the objective assessment of whether the child is actually wheezing

Expected Outcomes:

Year 1

·      Development of the experimental assays and techniques and collection of the initial cohort of patients.

·      Recruitment of the healthy controls

·      Literature review of the current underpinning evidence that will form the basis of the PhD introduction

Year 2

·      Analysis of the baseline samples

·      Collection of samples 12 months post initial illness to review for changes

·      Consideration of the potential for additional projects on susceptibility to infection

·      WheezeScan use with in the patients who develop wheezing illness

Year 3

·      Collection of final samples

·      Write up of PhD and preparation for publication

Funding Notes:

The Trustees of The Medical College of Saint Bartholomew’s Hospital Trust (MCSBHT) have offered funding for a research studentship, for a clinically qualified candidate to commence in October 2023, leading to a PhD degree from The QMUL Faculty of Medicine and Dentistry.

This studentship will fund a student with a clinical qualification and GMC / GDC registration at any career stage below consultant. The Studentship will cover the successful candidate’s current clinical salary and will include PhD fees (at home fee rate) with up to £6000 pa for consumables. Further consumables / funding for travel may be available on application. 

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