# Breath Analysis: A Promising Tool for Disease Diagnosis--The Role of Sensors
###### Abstract  
Early-stage disease diagnosis is of particular importance for effective patient identification as well as their treatment. Lack of patient compliance for the existing diagnostic methods, however, limits prompt diagnosis, rendering the development of non-invasive diagnostic tools mandatory. One of the most promising non-invasive diagnostic methods that has also attracted great research interest during the last years is breath analysis; the method detects gas-analytes such as exhaled volatile organic compounds (VOCs) and inorganic gases that are considered to be important biomarkers for various disease-types. The diagnostic ability of gas-pattern detection using analytical techniques and especially sensors has been widely discussed in the literature; however, the incorporation of novel nanomaterials in sensor-development has also proved to enhance sensor performance, for both selective and cross-reactive applications. The aim of the first part of this review is to provide an up-to-date overview of the main categories of sensors studied for disease diagnosis applications via the detection of exhaled gas-analytes and to highlight the role of nanomaterials. The second and most novel part of this review concentrates on the remarkable applicability of breath analysis in differential diagnosis, phenotyping, and the staging of several disease-types, which are currently amongst the most pressing challenges in the field. breath analysis; volatile organic compounds; sensors; nanomaterials; differential diagnosis 20  
breath condensates (e.g., peroxynritrite, cytokines, and isoprostanes) constitute the human breath [1; 9; 10]. Decreased sample complexity, the highly developed appropriate analytical techniques, and the ability of direct or continuous breath analysis using gas sensors render exhaled breath as an exceptional source of gas-biomarkers (VOCs predominantly but also inorganic gases) [8; 11]. More than 2000 VOCs have been detected in the exhaled breath [12] and appertain to hydrocarbons, alcohols, aldehydes, ketones, esters [12; 13], ethers, carboxylic acids, heterocyclic hydrocarbons [12], aromatic compounds, nitriles [12; 13], sulfides, and terpenoids [12] and may be endogenous or exogenous. Exogenously originated VOCs are correlated with the environment and the habits of the person [14]. VOCs related with cleaning fluids, personal care products, plastic-related VOCs [14], blazes, or air pollution due to industrial/transport gas emissions [12] enter human organism through extended inhalation and are excreted via exhaled breath. Smoking [15], food habits and food supplements, drinks, or medication also consist important sources of VOCs [14; 15]. Other important confounding factors affecting the profile of exhaled VOCs are age, gender, ethnicity, living place, and lifestyle [15; 16]. Consequently, immediate and recent environmental exposure should be taken into consideration during breath analysis [14]. Endogenously created VOCs comprise high vapor pressure (body and room temperature (RT)) (fragments of [14]) byproducts of normal or pathophysiological metabolic pathways [7; 14; 17], as well as of microbiome metabolism [14]. They are produced either in the airway region or in other parts of human body, representing the metabolism of the whole organism. In the first case, VOCs are released in the exhaled breath in a direct way [17]. In the second case, produced VOCs enter and circulate in the bloodstream, and, during gas exchange in the alveoli or the airways, excretion to the exhaled breath occurs [15; 17] via the alveolar pulmonary membrane [9; 10]. Depending on blood solubility, VOCs are exchanged in different sites of the respiratory tract. Nonpolar VOCs with poor blood solubility (blood-air partition coefficient (\(\lambda_{bx}\)) \(<\) 10) are exchanged in the alveoli, in contrast to blood soluble VOCs (\(\lambda_{bx}\) \(>\) 100) that are exchanged in lung airways. VOCs of intermediate solubility (10 \(<\lambda_{bx}\) \(<\) 100) undergo pulmonary gas exchange in both sites [12; 15].