Pre-clinical Diagnosis Using Integrated Microbial and Host Response Signatures to Improve Outcomes From Ventilator-associated Pneumonia in Critically Ill Children

Overview

Ventilator-associated pneumonia (VAP), defined as pneumonia occurring 48 hours after initiation of invasive mechanical ventilation, is insidious in onset and severe in consequence. It is a critical issue affecting 10-20% of the 26,000 children admitted to the paediatric intensive care unit (PICU) each year. Infection typically leads to extended PICU stay, prolonged invasive mechanical ventilation, and increased mortality. Despite its clinical significance, VAP remains poorly defined, as current diagnosis relies on non-specific criteria and the ability to obtain clinically meaningful cultures. VAP, deviates from conventional pneumonia, potentially originating, from tissue damage, changes to immune processes, and migration of gastrointestinal bacteria into the lung; all associated with prolonged mechanical ventilation. These factors, in combination with the clinical instability of PICU patients, mean that clinicians aggressively start antibiotic therapy despite a paucity of evidence to suggest the best regime. As a result, suspected VAP has been shown to account for nearly 40% of antibiotic exposure in the PICU, which has significant implications on anti-microbial resistance (AMR). To address these challenges, novel diagnostic therapies are needed to optimise the treatment of VAP. These therapies should utilise our current understanding of the pathophysiology of VAP development, specifically, the infiltration of the lung microbiome by gut and oral bacteria during prolonged mechanical ventilation. To achieve this, molecular testing should be promoted allowing for rapid identification of lung pathogens. There is also growing evidence, for the investigation of predictive biomarkers for VAP available in both the blood and lungs, which when integrated into protocols may enhance diagnostic accuracy. These novel techniques may improve clinical outcomes for affected children while addressing the economic impact of prolonged hospital stays and mitigating AMR risks in PICUs.

Primary outcome measures

• Characterise temporal shifts in microbial composition and the corresponding host immune response during prolonged mechanical ventilation [Time frame: 3 years]
• Characterise the AMR burden in VAP and its role in shaping the microbiome during infection. [Time frame: 3 years]
• Develop statistical and/or machine learning models leveraging these signatures independently, or in combination, to identify putative microbial and host biomarkers for early VAP diagnosis [Time frame: 3 years]

Secondary outcome measures (6)

• Prevalence of VAP [Time frame: 3 years]
• 30 day mortality [Time frame: 3 years]
• Time To Extubation [Time frame: 3 years]
• Utilisation Of VAP Prevention Bundle [Time frame: 3 years]
• Culture Results [Time frame: 3 years]
• Days free of antimicrobial therapy in PICU at 7 days [Time frame: 3 years]

Eligibility criteria

Inclusion criteria

• PICU Admission
• Requires 48 Hours Of Mechanical Ventilation

Exclusion criteria

• Imminent death or palliative care pathway planned
• Existing tracheostomy at time of admission
• Known immunocompromised patient
• Patient received a full course of systemic antimicrobials in the previous 6 weeks.
• Known or suspected tuberculosis (TB).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

United Kingdom · 1 center

• Cambridge University Hospitals NHS Foundation Trust — Cambridge

Identifiers

NCT: NCT07026656 · IRAS number: 333103

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗