Differentiating infection, colonisation, and sterile inflammation in critical illness: the emerging role of host-response profiling

Infection results when a pathogen produces host tissue damage and elicits an immune response. Critically ill patients experience immune activation secondary to both sterile and infectious insults, with overlapping clinical phenotypes and underlying immunological mechanisms. Patients also undergo a shift in microbiota with the emergence of pathogen-dominant microbiomes. Whilst the combination of inflammation and microbial shift has long challenged intensivists in the identification of true infection, the advent of highly sensitive molecular diagnostics has further confounded the diagnostic dilemma as the number of microbial detections increases. Given the key role of the host immune response in the development and definition of infection, profiling the host response offers the potential to help unravel the conundrum of distinguishing colonisation and sterile inflammation from true infection. This narrative review provides an overview of current approaches to distinguishing colonisation from infection using routinely available techniques and proposes matrices to support decision-making in this setting. In searching for new tools to better discriminate these states, the review turns to the understanding of the underlying pathobiology of the host response to infection. It then reviews the techniques available to assess this response in a clinically applicable context. It will cover techniques including profiling of transcriptome, protein expression, and immune functional assays, detailing the current state of knowledge in diagnostics along with the challenges and opportunities. The ultimate infection diagnostic tool will likely combine an assessment of both host immune response and sensitive pathogen detection to improve patient management and facilitate antimicrobial stewardship.