## 2 Exhaled Breath (EB) Analysis  
Breath analysis is possibly one of the oldest forms of diagnosis. Its usage for disease diagnostics dates back to ancient Greeks where physicians used EB to diagnose different diseases [5; 6]. Breath odours allow correct associations to certain diseases. For example, the sweet smell of diabetic ketoacidosis, the rancid odour of _C. difficile_ stools [6], the fishy smell of breath associated to liver illness, the urine-like odour of kidney disease, the grapes flavour of _Pseudomonas_ infections [5; 7] or the sewer smell of the breath of patients with lung abscesses, caused by the proliferation of anaerobic bacteria [8; 9; 10; 11]. The reason behind this capability is certainly the powerful human olfactory system that [PERSON] _et al._[12] recently demonstrated to be able to discriminate at least 1 trillion different olfactory stimuli. EB composition reflects the volatile composition of the bloodstream, and its composition can be correlated with the arterial concentration of the same analytes, although we have to consider that some volatile compounds are originated in the airways, not being present in the blood (as nitric oxide, for instance) [13]. Regardless of their origin, it would be very difficult to detect most of the volatiles directly from blood samples [14]. EB is mainly composed of nitrogen (N2), oxygen (O2), carbon dioxide (CO2), water vapour and inert gases. O2 and CO2 diffuse passively between blood and breath according to their concentration gradients across the alveolar-capillary junction, dragging together thousands of other very low abundant volatile organic compounds (VOCs), as long as they exhibit significant vapour pressures [15]. These VOCs, estimated in over 3000, account for less than 100 parts per million (ppm) of the total breath volume [13, 16, 17], although part of them, as acetone, isoprene and propanol, are more abundant, existing in the ppm to sub ppm range, while ketones, aldehydes and pentane, for instance, occur at even lower concentrations, at the parts per billion (ppb) to parts per trillion (ppt) levels [18, 19, 20, 21]. It is precisely the combination of these VOCs that define the \"smell\" of EB. Many of them are systemic or endogenous, being produced in physiological processes, but the metabolic routes behind their production are known only for a very limited number of VOCs (reviewed in [13]). Other VOCs are exogenous and result from external contamination through the inhaled air or ingested foods or drinks. These are considered as pollution or background noise [22]. Unfortunately, this seems to be the case for most VOCs. [PERSON] _et al._[10] analysed the EB from 50 normal individuals and processed the data obtained considering that only the VOCs with positive alveolar gradient (concentration higher in breath than in air) are more likely to be endogenous and not inhaled from external environment through the lung. They found that only half of the 340 VOCs identified fulfilled this condition. Moreover, they also reported a broad sample variation, because only 27 of these endogenous VOCs were present in all individuals [10]. This result is illustrative of the complexity of the EB samples and the existence of many contaminants originated by the ambient surroundings. In addition there are also other problems related with the subject or the analytical approach selected, as discussed by [PERSON] _et al._[23] for VOCs analysis in pulmonary diseases. Regarding the environmental influence, besides the contamination with ambient VOCs, the abundance of CO2 and water vapour in exhaled air, is particularly challenging as water condensation interferes with the quantification of low abundant VOCs, particularly alcohols and aldehydes [24].