Developmental Clinical Studies-validation of the utility of a novel smartprobe detecting neutrophil activation/elastase activity in acute lung injury

40% of all patients in the intensive care unit (ICU) need a ventilator to support their lungs, with many associated complications. Currently the main indication of clinical deterioration is the presence/spreading of shadowing on the chest x- ray. This has many different causes (all requiring different treatments). There is a pressing need for rapid bedside tests to provide definitive diagnostic information about what is happening in the lungs themselves. Many studies have used blood markers, but in patients with multi-system disease these are not specific for the lung and the results are too slow to be useful in the rapidly-changing ICU setting.
We will employ cutting-edge technology to pass a tiny optical fibre deep into the lungs of ventilated patients and spray a 'microdose' of an imaging agent that will tell us the reasons for the lung deterioration. This approach has the potential to rapidly determine, at the bedside, if the lung shadowing is due to inflammation. Such an approach could revolutionise the way we deal with the critically ill patient and provide rapid, point of care diagnostics that would help tailor the patient's management.

a) Healthcare need addressed:
To allow clinicians in intensive care units (ICU) to rapidly and accurately determine the aetiology of deteriorating respiratory function or clinical status suggested, for example, by new infiltrates on the chest x-ray (CXR).
b) The technology/solution:
We will employ a combined approach utilising recent advances in bronchoscopic confocal imaging for bedside-based, in situ real-time imaging together with the local, microdosed, instillation of next-generation 'smart' molecular probes targeting neutrophil activation (NAP). This will allow patient delineation for specific drug targeting and stratify/inform clinicians immediately for prognosis: specifically the presence and activity of neutrophils.
c)Methodology:
The study will be conducted in two phases. The first involves administering NAP to healthy volunteers with experimental lung inflammation. The second phase moves to a 100-patient clinical study in ICU. NAP will be delivered directly into inflamed lungs and 'heat maps' of pulmonary neutrophil dependent lung injury will be generated by pCLE.
d) Impact on healthcare:
Accurate, dynamic cellular/molecular diagnosis would lead to stratification of patient care and tailored prescribing patterns, including the use/non-use of expensive and potentially toxic anti-bacterials and ultimately reduced ventilator dependency and reduced mortality and morbidity in critically ill patients. This approach is applicable to disease detection/stratification/therapeutic intervention in other organs accessible by fibreoscopy.

Impacts on Patients, Patient Pathways: Rapid and accurate bedside testing for pulmonary inflammation is a "holy grail" for modern critical care. Currently clinicians are faced with significant uncertainty in relation to triggers to commence treatment, the choice of agents, and especially the clinical confidence to de-escalate therapy. These issues are barriers to effective antibiotic stewardship, because of the proven association between delayed and inadequate antibiotic therapy and adverse clinical outcomes. Direct, bedside pulmonary molecular imaging provides the potential to break this cycle of uncertainty at an early stage, resulting in more appropriate antibiotic use, improved clinical outcomes, and reduced financial burden to healthcare organisations.

Greater characterisation of pulmonary inflammation in real-time provides the potential to target existing and novel therapies and detect early predictors of clinical response. For example, despite negative clinical trials, steroids are widely used in ALI. Smartprobes offer the potential to improve the risk/benefit profile of steroid therapy and other existing and new therapies by enabling cell-specific effects to be measured in the individual patient. Similar approaches have been proposed for sepsis therapies based on point-of-care blood tests, but these have flaws (outlined above) and our proposed technology is a novel approach to directly characterise disease and its response to therapy deep in the human lung; the organ failing most frequently during critical illness.

A quantitative estimate of the scale of potential benefits at a population level is difficult to assess but given that 40% of all ventilated patients have a diagnosis of ALI/ARDS and there are no current strategies for monitoring therapeutic efficacy of interventions or stratifying patients, this technology offers a unique opportunity to ICU, and the potential healthcare benefits are likely to be considerable. Given the unmet need in ICU, we foresee no major barriers to the translation of this technology in multi-centre trials and subsequent widespread clinical application. The equipment is truly 'bedside' and the proposed programme of research will generate sufficient quantities of each probe to study up to 10,000 patients.

Pharma are actively interested in screening drugs in in vivo, hence a major impact will be on the provision of cutting-edge assays to assess drug response in situ in patients with lung disease.

Regarding wealth formation for the public, there is a direct opportunity to take the products of this research into a new small business enterprise and create jobs to develop similar molecular optical imaging probes using the same development pathway. This technological approach to apply cutting-edge chemistry with state of the art physics to detect optical molecular signatures deep within human tissue in critically ill patients is internationally unique and brings significant scientific impact and prestige to the multidisciplinary UK team and health service framework prosecuting the work.