Title: Use of molecular profiling to determine optimal management for moderate to severe preschool wheeze
Funder: Department of Health and Social Care

Abstract: Rationale: Up to one-third of children bacterial infections, not viruses, as was once thought. Therefore, use of antibiotics in children with bacterial infection may be most appropriate, but is currently not recommended. Hypothesis: Targeted treatment of preschool wheeze determined by airway inflammation and infection will result in better outcomes including fewer unscheduled healthcare visits improved health related quality of life (HRQOL) for the child and family, and lower health care costs compared to using current clinical guidelines. Objectives: 1. To compare management of moderate to severe recurrent wheezing in preschool children aged 1-5 years using a regimen guided by evidence of airway eosinophilic inflammation and bacterial infection to the current recommended clinical guidelines based on symptom pattern. 2. To determine relationships between invasive assessments of eosinophilic airway inflammation (broncho-alveolar lavage and endobronchial biopsy) and non-invasive assessments (induced sputum, exhaled nitric oxide (FeNO) and blood) in severe wheezers undergoing a clinically indicated bronchoscopy. 3. To assess the utility of molecular biological techniques (16SPCR) to identify airway microbes compared to traditional culture in guiding treatment of infection induced wheezing. Design: The overarching work is a randomised trial to compare molecular phenotype based management to current clinical guidelines based management in children aged 1-5 years hospitalised with >2 episodes of wheeze in the previous 6 months. Eosinophilic inflammation will be assessed using induced sputum or blood eosinophils. Infection will be assessed by culture of sputum or oropharyngeal swabs. In the molecular phenotype management group those with eosinophilic inflammation will be treated with regular inhaled steroids and bacterial infection will be treated with a prolonged course of targeted antibiotics. Clinical guidelines based management will continue in the control group. Outcomes: Primary outcome: unscheduled healthcare visits. Secondary outcomes: HRQOL for the child and family, hospitalisations, days of oral steroids for acute symptoms. This study will also provide novel data relating invasive and non-invasive assessments of airway inflammation in preschool children, and direct comparisons of bacterial cultured organisms and the airway microbial flora detected by PCR. Healthcare benefits: Exacerbations requiring unscheduled healthcare visits or hospitalisation are the main clinical feature of preschool wheezing disorders. The median age of children admitted with acute wheeze or asthma in the UK is 3 years and the healthcare costs of managing children between 1-5 years with wheeze was approximately 53million in 1998/9, most of which was incurred by emergency healthcare. If management based on molecular phenotype results in fewer unscheduled healthcare visits, this will result in a significant reduction in use of healthcare resources. This approach will be easily applicable to clinical practice as it does not involve new or unlicensed therapies, but adopts a new approach to deciding treatment using objective biomarkers.

Lay abstract: One-third of all preschool children have frequent wheezing and breathlessness which is very difficult to treat. Currently, symptom pattern is used to decide treatment, but this is very crude and inexact. Some preschool wheezers have inflammation caused by cells called eosinophils in their blood and airways, while others have bacterial infection. This project will determine whether precisely targeting treatment according to the presence or absence of inflammation and infection is better than using symptoms alone. The impact on need for emergency healthcare and quality of life for the child and family will be used to determine which approach is better.

Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: RESPIRATORY;INFLAMMATORY AND IMMUNE SYSTEM;INFECTION