Guided by Breath Breath is an important indicator of an individual’s health, now researchers are looking to use it as a means of both diagnosing disease and optimizing drug dosage. This could represent an important step towards personalised medicine, enabling medical staff to monitor the effects of drugs over time and tailor treatment more precisely to individual needs, as Professor Pablo Sinues explains. The problem: narrow therapeutic window; highly individual-specific response
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Breath analysis
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Proposed solution: therapeutic drug monitoring guided by real-time breath analysis
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bacterial infection – go down after antibiotic administration, thus enabling a way to firstly diagnose, hence helping to choose the right treatment, and secondly monitor the response to this intervention” explains Professor Sinues. The goal in the project is to prove that breath analysis can be used to diagnose pnenumonia, with a view towards eventually applying this approach in the clinic, although Professor Sinues sees it more as complementary to existing methods rather than as a replacement. “I see it first of all as a very rapid screening method. My goal is not to replace current methods, it’s simply to provide complementary information,” he stresses. “Currently there are molecular methods that work very well, but have certain limitations that we may be able to overcome in a complementary fashion.”
We have two main research lines in my lab. One is dedicated to trying to detect medication in breath, and to trying to correlate these breath values with the systemic concentrations of these drugs. The second is the diagnosis of pneumonia. Drug Dosage
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A lot of attention in research is devoted
Breath Analysis
to enabling rapid diagnosis and more tailored treatment, part of the wider shift towards personalised medicine. Analysis of an individual patient’s breath could be an important diagnostic tool, as well as in assessing the correct drug dosage for treatment, topics that Professor Pablo Sinues is addressing in two new projects supported by the Swiss National Science Foundation (SNSF). “We have two main research lines in my lab. One is dedicated to trying to detect medication in breath, and to trying to correlate these breath values with the systemic concentrations of these drugs. The second main research topic is the diagnosis of pneumonia,” he explains. Secondary Electrospray Ionization (SESI) technique, which is used together with high resolution mass spectrometers, plays a central role in this work. “We can detect a wide range of metabolites in exhaled breath, providing a comprehensive, noninvasive overview of relevant biochemical activity taking place in our bodies. We can do this in real time, enabling rapid patient assessment,” continues Professor Sinues.
This opens up the possibility of using breath analysis to rapidly identify which specific pathogen causes pneumonia, which would be a significantly more efficient approach than current methods. The hypothesis behind this work is that the pathogens which infect the respiratory system produce their own suite of metabolic end-products, which are not normally present (or are present at relatively low levels) in healthy people. “There are clear indications suggesting that microbes produce ‘exotic’ metabolites different to what we produce naturally,” outlines Professor Sinues. There is a high level of heterogeneity in breath profiles among the wider population, so researchers are analysing large volumes of data to identify the markers associated with pneumonia. “We are analysing data from different sites in Switzerland, as well as from China,” says Professor Sinues. “We will make sure the data is gathered with the same procedures, then we will pool the data and extract information from high quality datasets acquired across all laboratories placed in clinical settings.” The ultimate goal here would be to relate the
presence of a particular metabolite – or group of metabolites – in the breath to a particular pathogen. Several in vitro studies have been carried out, on the basis of which researchers hope to not only help diagnose pneumonia, but also narrow down which pathogen or group of pathogens are responsible in each case. “This is important, because then it will be easier to provide the right treatment,” stresses Professor Sinues. This could bring important benefits, as currently it is quite difficult to know beforehand the responsible pathogen(s), so patients are often treated with fairly generic antibiotics, which may not be ideal. “It may not turn out to be the right choice, then this has consequences for antibiotic resistance,” points out Professor Sinues. “We are trying to build a more comprehensive picture of the characteristics of the pathogen.” This will provide the basis of a more personalised approach to treatment, while breath analysis could also play an important role in monitoring the effectiveness of interventions. If a treatment is effective, then it would be marked by the decline of certain markers in the breath. “We would expect to see these signals – associated for example to
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information there and then, rather than waiting two days until this information is available.” This is particularly important with drugs that have a very narrow therapeutic range, where too high a dosage would be toxic to the patient, and too low would be ineffective. Researchers aim to generate models that will enable medical staff to automatically calculate – on the basis of a breath test – the systemic concentration of a drug, which can then be used to guide decisions about dosage. “There is a clear clinical need to look at these drugs, to optimise the dosage of these drugs for patients. It’s also important to consider clinical and toxic effects. Is this drug really working or not?” points out Professor Sinues. Several different drugs will be investigated within the project, and while Professor
A second major priority in Professor Sinues’ group is to use breath analysis to quickly and accurately assess the systemic concentration of drugs in the body, which is enormously important in determining the right dosage of medication to treat children with certain conditions, for example epilepsy and cancer. Currently, children with epilepsy have to provide quite large volumes of blood during a consultation, the results of which may not be available for several days, whereas a reliable breath test would be much quicker and more patient-friendly. “We aim to screen patients that require monitoring of the levels of therapeutic drugs,” outlines Professor Sinues. “The idea is that, in future, neurologists (in the case of epilepsy patients) will have the result on the same day as the consultation, so they can make clinical decisions on the basis of this Project Team
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Sinues does not expect it will be possible to precisely assess the concentrations of all of them from breath analysis, he is confident that this research will bring wider benefits. “We are looking into bringing this concept to the market,” he says. “A start-up company named Deep Breath Initiative was launched at the University of Basel earlier this year to accomplish this endeavour.” This work is very much in line with the wider trend towards personalised medicine, and the goal of adapting and tailoring treatment more precisely to the specific needs of individual patients. The human population is quite heterogenous and one treatment doesn’t necessarily fit all, a major motivating factor behind Professor Sinues’ work. “We aim to understand the response of patients to an intervention, to try and optimise subsequent interventions,” he outlines.
Guided by Breath Individualized Drug Dosage Guided by Breath Project Objectives
The objective in this new project is to optimize the therapeutic regimen of pediatric patients to maximize drug efficacy and minimize side effects. This will be achieved by developing a mass spectrometry-based breath test. Ultimately, this will lead to new opportunities to guide the dosage of drugs with high precision, in real-time and in a patient-friendly fashion.
Project Funding
University Children’s Hospital Basel (UKBB) http://www.snf.ch/en/funding/careers/ eccellenza/Pages/default.aspx The two SNSF grants are: Pneumonia 320030_173168; Diagnosis of Bacterial Pneumonia by Exhaled Breath Analysis; Duration 4 years, budget 690,000 CHF. Drugs PCEGP3_181300; Individualized Drug Dosage Guided by Breath Analysis; Duration 5 years, budget 1,500,000 CHF. This is a prestigious Eccellenza grant
Project Partners
• Profs. Malcolm Kohler and Annelies Zinkernagel (University Hospital Zurich) • Prof. Alexander Möller (University Children’s Hospital Zurich) • Profs. Nicolas von der Weid, Johannes van den Anker, Urs Frey and PD Alexandre Datta (University Children’s Hospital Basel)
Contact Details
Project Coordinator, Prof. Dr. Pablo Sinues, PhD Tenure Track Assistant Professor University Children’s Hospital Basel (UKBB) Department of Biomedical Engineering University of Basel Spitalstrasse 33 | CH-4056 Basel Switzerland T: +41 61 704 29 49 E: pablo.sinues@ukbb.ch W: www.sinueslab.dbe.unibas.ch Professor Pablo Sinues
Professor Pablo Sinues holds a master’s in chemistry, and a PhD in mechanical engineering. Visiting PhD and Postdoc at Yale University in former lab of Nobel Prize awardee Prof. John B. Fenn. Habilitation in analytical chemistry at the ETH Zurich. Since 2017 Tenure-Track Assistant Professor position at the University of Basel (Department of Biomedical Engineering).
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