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Bedside monitoring of infection based on exhaled breath

Final Report Summary - BREATHDX (Bedside monitoring of infection based on exhaled breath)

Molecular analysis of exhaled breath is a new frontier in medical testing with an enormous potential for monitoring respiratory diseases. Breath tests are non-invasive and require minimal to no patient efforts. This makes them applicable in a wide range of settings varying from the home to the intensive care unit (ICU) setting.
Respiratory infections are the primary cause of death in ICU. Many patients in ICUs worldwide suffer from infections, which lengthen their hospital stays and increase their mortality rate. Timely detection and treatment is important and monitoring infection via breath analysis will have a major impact on outcome.
Presently, state of the art breath analysis includes gas chromatography and mass spectroscopy (GC-MS), which is a bulky lab technique that is valid, though very expensive, slow, labor-intensive, and it requires specific expertise from an operator. Electronic nose sensor technology is being developed based on pattern recognition of composite molecular mixtures, but there is a need for clinical validation. Also the sensitivity of the sensors should be tailored towards particular medical applications. In this proposal the focus is on developing a sensor technique, where measurements are obtained and processed at the bedside. This solution will be dedicated to the detection of infection from breath.
BreathDx focusses on a synergistic approach between (a) sensor technology development, (b) clinical validation and (c) interpretation of complex data. Knowledge is exchanged between an industrial partner (Philips, NL) strongly involved in the healthcare market, two academic partners (University of Manchester (UoM), UK, Academic Medical Center (AMC), NL) that have an impressive track record in breath analysis research in a clinical environment and the university of Twente (UT, NL) that has potential on bedside gas sensor technology that can be tailored to compounds and applications of interest.
The main research goals of the BreathDx project are:

1. Understanding of the composition of breath related to respiratory infection in invasively ventilated ICU patients;

2. Develop smart signal processing strategies for interpretation of complex rich data-samples; and

3. Develop and validate bedside gas sensor technology that can be tailored to compounds of interest dedicated to compounds in human breath

Due to the multi-disciplinary nature of the domain area of breath analysis research, close co-operation between sensor development, analytical chemistry, clinical expertise and data analysis is essential for developing an optimal solution. The BreathDx consortium already has been proven to be an excellent foundation to foster a longer-lasting collaboration between the partners involved.
A summary of results:
The transfer of knowledge between Philips, UT, AMC UoM accelerated the development of breath analysis solutions for infection detection in the ICU setting.
The BreathDx consortium set up a multicenter clinical study for collecting breath samples in a total of 150 ICU patients with a respiratory infection. An important deliverable and milestone is that the clinical study protocol has been completed and ethics approval was granted. The study started on May 26th 2015 at the AMC in NL, where the first patient was included and breath samples were successfully collected. The study started in the University Hospital South Manchester on December 1st 2015, on May 10th 2016 at Salford Royal Foundation Trust, and on June 20th 2016 in Central Manchester University Hospital, three hospitals located in or near Manchester, UK.
The study is running steadily and 90 patients have been enrolled so far. At the AMC so far were 45 patients included (one was withdrawn). In Manchester, so far 45 patients were included.
Inclusion rate has been slower than expected; In order to speed up the inclusion the BreathDx consortium is collaborating with two additional clinical centers that joined our study in 2017. One extra site in the Netherlands, and one additional site in Portugal. Due to the slow inclusion rate data collection is still ongoing and planned to stop in March 2018. All partners involved agreed in this prolongation of this study in order to reinforce the output and impact of BreathDx.
Analysis of the breath data shows good quality breath data. In a few samples ethanol is distorting the signal. This is used as feedback in the sampling procedure, to take extra care using ethanol for cleaning immediately prior to sampling.
The collection and analysis of breath samples are still in their infancy and today there is no standardized method available to capture and store breath samples. Therefore within the consortium an optimal breath sampling methodology was developed.
Besides collecting patient breath data, the consortium has worked on in vitro experiments studying volatile organic compounds coming from pathogens involved in ventilator associated pneumonia.
The microelectromechanical sensor, built for detection of VOCs in breath, has undergone several improvements. Important insights have been obtained on electronic, mechanical and chemical properties. The sensor has been redesigned to allow mass fabrication and high throughput use, involving technologies such as large area deposition of piezoelectric films, electronic readout based on resonant frequency tracking and inkjet printing of surface chemistries.
An electronic readout system was realized together with a graphical user interface. Experiments were carried out to test the sensor and electronic readout system. A demonstrator setup is available that can readout 8 cantilever signals simultaneously. The cantilever array sensors are able to detect specific volatile organic compounds using fingerprint response patterns.