For a small fraction of all therapeutic drugs currently used, routine monitoring is crucial. The reason for this is that the gap between therapeutic and toxic concentration is very narrow. This, combined with the fact that there exists high inter-individual variability, has led to the need for therapeutic drug monitoring (TDM). The goal of TDM is to individualize the dosage to achieve maximum efficacy and at the same time minimize drug toxicity. TDM has obvious clinical benefits for patients and healthcare systems. However, TDM in children is particularly challenging. In addition, traditionally used venipunctures to determine drug concentrations are not well tolerated by children. The goal of this project is to address these challenges by providing a non-invasive and patient-specific solution, whereby drugs requiring TDM in children will be monitored in exhaled breath. We will use a cutting-edge analytical platform (i.e. secondary electrospray ionization-mass spectrometry) available at the University Children's Hospital Basel to detect drugs in breath with unparalleled speed, selectivity and sensitivity. Initially, we will measure simultaneously blood and breath concentrations of drugs routinely monitored in our hospital (e.g. anti-convulsants). We will then use this information as an input to develop pharmacokinetic computational models to predict blood concentrations based on the breath test read-out. During the final phase, we will validate these models in an independent group of patients to proof the clinical transferability of breath-based tests to guide drug dosage on an individual basis. This project will have a tremendous impact on current pediatric TDM clinical practice by: i) enabling a more personalized treatment, hence reducing ineffective doses and adverse effects; ii) improving patients' outcome; iii) saving hospital costs and iv) gaining new insights on pharmacokinetic aspects such as key parameters governing the diffusion of drugs in the lungs.

Exposure of children to environmental tobacco smoke (ETS) can lead to serious health consequences, impairing lung development, and increasing the risk for respiratory disease in adulthood. While there is strong evidence confirming detrimental effects of ETS from clinical observational studies, much remains unknown at the molecular level which could improve our understanding of the mechanisms by which ETS affects respiratory health. ETS has been associated with alterations in cell signaling, ultimately causing impaired cellular growth in lung tissue. The objective of this project is to identify exhaled markers altered as a result of ETS exposure, thus gaining insights on the detrimental effects of ETS. We will measure cotinine levels using standard analytical methods to objectively assess the level of exposure on an individual basis. We will seek associations between systemic cotinine concentrations and exhaled metabolite levels. Obtaining evidence of the detrimental effect of ETS exposure in the respiratory system as assessed by exhaled metabolites will provide a valuable input to public health policymakers.

Wir wissen aus mehreren Studien, einschließlich der BILD-Studie, dass die Luftverschmutzung im frühen Kindesalter Auswirkungen auf die kindliche Entwicklung der Lunge hat. Untersuchungen in Ländern mit hoher Luftverschmutzung haben gezeigt, dass die Exposition mit bestimmten Luftschadstoffen zu einer Beeinträchtigung des Lungenwachstums und der Entwicklung von Asthma führen kann. Selbst eine geringe Luftverschmutzung während der Schwangerschaft kann Auswirkungen auf die Lungenfunktion eines Säuglings kurz nach der Geburt haben. Wir wollen untersuchen ob in dieser frühen Phase der Lungenentwicklung kurz vor und nach der Geburt das Lungengewebe durch Umweltreize geschädigt oder das Immunsystem beeinflusst wird. Auch wenn noch nicht ganz klar ist, wie dies geschieht, glauben wir, dass mehrere Faktoren dazu beitragen. Wir untersuchen beispielsweise die Rolle der erblichen Veranlagung, des Geburtsprozesses, der Ernährung, früher Infektionen und der Interaktion von Genen und Umweltschadstoffen. Jeder einzelne dieser Faktoren hat eine relativ geringe Auswirkung, aber zusammen können sie potentiell bestimmen, ob ein Kind Lungenkrankheiten oder Asthma entwickeln wird. In dieser aktuellen Phase unserer Studie interessiert uns vor allem, wie diese Umweltfaktoren das Wachstum, die Alterung, aber möglicherweise auch das vorzeitige Absterben von Lungenzellen beeinflussen. Dies könnte eine wertvolle zusätzliche Information sein, um zu verstehen, wie Umwelteinflüsse Wachstum und Entwicklung der Lunge beeinflussen.

Pneumonia is a severe infectious disease and a leading cause of hospitalization and death. It exacts an enormous cost in economic and human terms. Timely diagnosis is crucial for the outcome of therapy and health care associated costs. However, the high morbidity and mortality of pneumonia is partly due to the lack of efficient diagnostics. Animals with an excellent sense of smell (e.g. dogs) are capable of identifying bacterial infections by sniffing out sputum samples or even the air surrounding the infected patient. We thus hypothesize that pneumonia caused by bacterial agents can be identified by analyzing characteristic volatile metabolites produced during infection in the lung, which are eventually exhaled in breath. The goal of this project is to rapidly (within 15 min) diagnose bacterial pneumonia using a breath test. Additionally, the test should be capable to identify a subset of responsible pathogens. We will deploy an innovative mass spectrometric breath analysis technique (secondary electrospray ionization-mass spectrometry; SESI-MS) in a clinical setting. SESI-MS combines real-time response and unparalleled sensitivity (parts-per-trillion) and selectivity (~300 compounds per breath sample). We hypothesize that such a comprehensive metabolic fingerprint will provide an accurate pathogen-specific signature. We will combine cutting-edge analytical techniques, bioinformatics, mice models and access to well characterized patients in a multidisciplinary approach to elucidate and quantify exhaled metabolites that are indicators of pneumonia. This will significantly improve the current clinical and epidemiological situation by: i) enabling pathogen-based antibiotic treatment (thus reducing antibiotic resistance); ii) improving patients' outcome; iii) saving costs by supporting evidence-based hospitalization/outpatient decisions and iv) identifying altered metabolic routes, thus gaining insights on the mechanisms by which pathogens circumvent the human immune system.

Light is known to unlock a cascade of physiological changes in living organisms, including humans. These processes mediate fundamental aspects of our lives as for example awake-sleep patterns. However, how exactly light induces these changes is poorly understood. One of the reasons is the difficulty to analyze such rapid changes of metabolites in body fluids. During this project we will investigate light-induced changes in metabolism. To do so, we will capture fluctuations of metabolites concentrations via a novel breath analysis technique. This method is non-invasive and allows for real-time analysis. Our goal is to understand the mechanisms of light-induced metabolism to ultimately determine optimal conditions of light exposure to improve its therapeutic effects. This therapeutic strategy is especially well-suited to treat circadian disorders in shift workers.