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Introduction: Breath Volatile organic compounds (VOCs) are promising biomarkers for clinical purposes due to their unique properties. Translation of VOC biomarkers into the clinic depends on identification and validation: a challenge requiring collaboration, well-established protocols, and cross-comparison of data. Previously, we developed a breath collection and analysis method, resulting in 148 breath-borne VOCs identified. Objectives: To develop a complementary analytical method for the detection and identification of additional VOCs from breath. To develop and implement upgrades to the methodology for identifying features determined to be “on-breath” by comparing breath samples against paired background samples applying three metrics: standard deviation, paired t-test, and receiver-operating-characteristic (ROC) curve. Methods: A thermal desorption (TD)-gas chromatography (GC)-mass spectrometry (MS)-based analytical method utilizing a PEG phase GC column was developed for the detection of biologically relevant VOCs. The multi-step VOC identification methodology was upgraded through several developments: candidate VOC grouping schema, ion abundance correlation based spectral library creation approach, hybrid alkane-FAMES retention indexing, relative retention time matching, along with additional quality checks. In combination, these updates enable highly accurate identification of breath-borne VOCs, both on spectral and retention axes. Results: A total of 621 features were statistically determined as on-breath by at least one metric (standard deviation, paired t-test, or ROC). A total of 38 on-breath VOCs were able to be confidently identified from comparison to chemical standards. Conclusion: The total confirmed on-breath VOCs is now 186. We present an updated methodology for high-confidence VOC identification, and a new set of VOCs commonly found on-breath. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is the most common respiratory disease in preterm and is still associated with increased mortality and morbidity. The great interest lies in identifying early biomarkers that can predict the development of BPD. This pilot study explores the potential of e-nose for the early identification of BPD risk in premature infants by analyzing volatile organic compounds (VOCs) in the exhaled breath condensate (EBC). Fourteen mechanically ventilated very preterm infants were included in this study. The clinical parameters and EBC were collected within the first 24 h of life. The discriminative ability of breath prints between preterms who did and did not develop BPD was investigated using pattern recognition, a machine learning algorithm, and standard statistical methods. We found that e-nose probes can significantly predict the outcome of "no-BPD" vs. "BPD". Specifically, a subset of probes (S18, S24, S14, and S6) were found to be significantly predictive, with an AUC of 0.87, 0.89, 0.82, 0.8, and p = 0.019, 0.009, 0.043, 0.047, respectively. The e-nose is an easy-to-use, handheld, non-invasive electronic device that quickly samples breath. Our preliminary study has shown that it has the potential for early prediction of BPD in preterms. [ABSTRACT FROM AUTHOR]

Introduction: Volatile organic compounds (VOCs) can arise from underlying metabolism and are detectable in exhaled breath, therefore offer a promising route to non-invasive diagnostics. Robust, precise, and repeatable breath measurement platforms able to identify VOCs in breath distinguishable from background contaminants are needed for the confident discovery of breath-based biomarkers. Objectives: To build a reliable breath collection and analysis method that can produce a comprehensive list of known VOCs in the breath of a heterogeneous human population. Methods: The analysis cohort consisted of 90 pairs of breath and background samples collected from a heterogenous population. Owlstone Medical's Breath Biopsy® OMNI® platform, consisting of sample collection, TD-GC-MS analysis and feature extraction was utilized. VOCs were determined to be "on-breath" if they met at least one of three pre-defined metrics compared to paired background samples. On-breath VOCs were identified via comparison against purified chemical standards, using retention indexing and high-resolution accurate mass spectral matching. Results: 1471 VOCs were present in > 80% of samples (breath and background), and 585 were on-breath by at least one metric. Of these, 148 have been identified covering a broad range of chemical classes. Conclusions: A robust breath collection and relative-quantitative analysis method has been developed, producing a list of 148 on-breath VOCs, identified using purified chemical standards in a heterogenous population. Providing confirmed VOC identities that are genuinely breath-borne will facilitate future biomarker discovery and subsequent biomarker validation in clinical studies. Additionally, this list of VOCs can be used to facilitate cross-study data comparisons for improved standardization. [ABSTRACT FROM AUTHOR]

Background: The multitude of metabolites generated by physiological processes in the body can serve as valuable biomarkers for many clinical purposes. They can provide a window into relevant metabolic pathways for health and disease, as well as be candidate therapeutic targets. A subset of these metabolites generated in the human body are volatile, known as volatile organic compounds (VOCs), which can be detected in exhaled breath. These can diffuse from their point of origin throughout the body into the bloodstream and exchange into the air in the lungs. For this reason, breath VOC analysis has become a focus of biomedical research hoping to translate new useful biomarkers by taking advantage of the non-invasive nature of breath sampling, as well as the rapid rate of collection over short periods of time that can occur. Despite the promise of breath analysis as an additional platform for metabolomic analysis, no VOC breath biomarkers have successfully been implemented into a clinical setting as of the time of this review. Aim of review: This review aims to summarize the progress made to address the major methodological challenges, including standardization, that have historically limited the translation of breath VOC biomarkers into the clinic. We highlight what steps can be taken to improve these issues within new and ongoing breath research to promote the successful development of the VOCs in breath as a robust source of candidate biomarkers. We also highlight key recent papers across select fields, critically reviewing the progress made in the past few years to advance breath research. Key scientific concepts of review: VOCs are a set of metabolites that can be sampled in exhaled breath to act as advantageous biomarkers in a variety of clinical contexts. [ABSTRACT FROM AUTHOR]

(1) Background: Colorectal cancer is one of the leading causes of cancer-related death, while early detection decreases incidence and mortality. Current screening programs involving fecal immunological testing and colonoscopy commonly bring about unnecessary colonoscopies, which adds burden to healthcare systems. The objective of this study was to provide an assessment of the diagnostic performance of an electronic nose serving as a complementary screening tool to improve current screening programs in clinical settings. (2) Methods: We conducted a case–control study that included patients from a medical center with colorectal cancer and non-colorectal cancer controls. We analyzed the composition of volatile organic compounds in their exhaled breath using the electronic nose. We then used machine learning algorithms to develop predictive models and provided the estimated accuracy and reliability of the breath testing. (3) Results: We enrolled 77 patients, with 40 cases and 37 controls. The area under the curve, Kappa coefficient, sensitivity, and specificity of the selected model were 0.87 (95% CI 0.76–0.95), 0.66 (95% CI 0.49–0.83), 0.81, and 0.85. For subjects at an early stage of disease, the sensitivity and specificity were 0.90 and 0.85. Excluding smokers, the sensitivity and specificity were 0.88 and 0.92. (4) Conclusions: This study highlights the promising potential of breath testing using an electronic nose for enabling early detection and reducing unnecessary treatments. However, more independent data for external validation are required to ensure applicability and generalizability.

Multiphoton electron extraction spectroscopy (MEES) is an advanced analytical technique that has demonstrated exceptional sensitivity and specificity for detecting molecular traces on solid and liquid surfaces. Building upon the solid-state MEES foundations, this study introduces the first application of MEES in the gas phase (gas-phase MEES), specifically designed for quantitative detection of gas traces at sub-part per billion (sub-PPB) concentrations under ambient atmospheric conditions. Our experimental setup utilizes resonant multiphoton ionization processes using ns laser pulses under a high electrical field. The generated photoelectron charges are recorded as a function of the laser's wavelength. This research showcases the high sensitivity of gas-phase MEES, achieving high spectral resolution with resonant peak widths less than 0.02 nm FWHM. We present results from quantitative analysis of benzene and aniline, two industrially and environmentally significant compounds, demonstrating linear responses in the sub-PPM and sub-PPB ranges. The enhanced sensitivity and resolution of gas-phase MEES offer a powerful approach to trace gas analysis, with potential applications in environmental monitoring, industrial safety, security screening, and medical diagnostics. This study confirms the advantages of gas-phase MEES over many traditional optical spectroscopic methods and demonstrates its potential in direct gas-trace sensing in ambient atmosphere. [ABSTRACT FROM AUTHOR]

IntroductionIndividuals with diabetes mellitus (DM) are at an increased risk of Mycobacterium tuberculosis (Mtb) infection and progressing from latent tuberculosis (TB) infection to active tuberculosis disease. TB in the DM population is more likely to go undiagnosed due to smear-negative results.MethodsExhaled breath samples were collected and analyzed using high-pressure photon ionization time-of-flight mass spectrometry. An eXtreme Gradient Boosting (XGBoost) model was utilized for breathomics analysis and TB detection.ResultsXGBoost model achieved a sensitivity of 88.5%, specificity of 100%, accuracy of 90.2%, and an area under the curve (AUC) of 98.8%. The most significant feature across the entire set was m106, which demonstrated a sensitivity of 93%, specificity of 100%, and an AUC of 99.7%.DiscussionThe breathomics-based TB detection method utilizing m106 exhibited high sensitivity and specificity potentially beneficial for clinical TB screening and diagnosis in individuals with diabetes.

Abstract Background Breath testing using an electronic nose has been recognized as a promising new technique for the early detection of lung cancer. Imbalanced data are commonly observed in electronic nose studies, but methods to address them are rarely reported. Objective The objectives of this study were to assess the accuracy of electronic nose screening for lung cancer with imbalanced learning and to select the best mechanical learning algorithm. Methods We conducted a case‒control study that included patients with lung cancer and healthy controls and analyzed metabolites in exhaled breath using a carbon nanotube sensor array. The study used five machine learning algorithms to build predictive models and a synthetic minority oversampling technique to address imbalanced data. The diagnostic accuracy of lung cancer was assessed using pathology reports as the gold standard. Results We enrolled 190 subjects between 2020 and 2023. A total of 155 subjects were used in the final analysis, which included 111 lung cancer patients and 44 healthy controls. We randomly divided samples into one training set, one internal validation set, and one external validation set. In the external validation set, the summary sensitivity was 0.88 (95% CI 0.84–0.91), the summary specificity was 1.00 (95% CI 0.85–1.00), the AUC was 0.96 (95% CI 0.94–0.98), the pAUC was 0.92 (95% CI 0.89–0.96), and the DOR was 207.62 (95% CI 24.62–924.64). Conclusion Electronic nose screening for lung cancer is highly accurate. The support vector machine algorithm is more suitable for analyzing chemical sensor data from electronic noses.

Due to their immediate exhalation after generation at the cellular/microbiome levels, exhaled volatile organic compounds (VOCs) may provide real-time information on pathophysiological mechanisms and the host response to infection. In recent years, the metabolic profiling of the most frequent respiratory infections has gained interest as it holds potential for the early, non-invasive detection of pathogens and the monitoring of disease progression and the response to therapy. Using previously unpublished data, randomly selected individuals from a COVID-19 test center were included in the study. Based on multiplex PCR results (non-SARS-CoV-2 respiratory pathogens), the breath profiles of 479 subjects with the presence or absence of flu-like symptoms were obtained using proton-transfer-reaction time-of-flight mass spectrometry. Among 223 individuals, one respiratory pathogen was detected in 171 cases, and more than one pathogen in 52 cases. A total of 256 subjects had negative PCR test results and had no symptoms. The exhaled VOC profiles were affected by the presence of Haemophilus influenzae, Streptococcus pneumoniae, and Rhinovirus. The endogenous ketone, short-chain fatty acid, organosulfur, aldehyde, and terpene concentrations changed, but only a few compounds exhibited concentration changes above inter-individual physiological variations. Based on the VOC origins, the observed concentration changes may be attributed to oxidative stress and antioxidative defense, energy metabolism, systemic microbial immune homeostasis, and inflammation. In contrast to previous studies with pre-selected patient groups, the results of this study demonstrate the broad inter-individual variations in VOC profiles in real-life screening conditions. As no unique infection markers exist, only concentration changes clearly above the mentioned variations can be regarded as indicative of infection or colonization. [ABSTRACT FROM AUTHOR]

Background: Breath testing using an electronic nose has been recognized as a promising new technique for the early detection of lung cancer. Imbalanced data are commonly observed in electronic nose studies, but methods to address them are rarely reported. Objective: The objectives of this study were to assess the accuracy of electronic nose screening for lung cancer with imbalanced learning and to select the best mechanical learning algorithm. Methods: We conducted a case‒control study that included patients with lung cancer and healthy controls and analyzed metabolites in exhaled breath using a carbon nanotube sensor array. The study used five machine learning algorithms to build predictive models and a synthetic minority oversampling technique to address imbalanced data. The diagnostic accuracy of lung cancer was assessed using pathology reports as the gold standard. Results: We enrolled 190 subjects between 2020 and 2023. A total of 155 subjects were used in the final analysis, which included 111 lung cancer patients and 44 healthy controls. We randomly divided samples into one training set, one internal validation set, and one external validation set. In the external validation set, the summary sensitivity was 0.88 (95% CI 0.84–0.91), the summary specificity was 1.00 (95% CI 0.85–1.00), the AUC was 0.96 (95% CI 0.94–0.98), the pAUC was 0.92 (95% CI 0.89–0.96), and the DOR was 207.62 (95% CI 24.62–924.64). Conclusion: Electronic nose screening for lung cancer is highly accurate. The support vector machine algorithm is more suitable for analyzing chemical sensor data from electronic noses. [ABSTRACT FROM AUTHOR]

Early detection of colorectal cancer is crucial for improving outcomes and reducing mortality. While there is strong evidence of effectiveness, currently adopted screening methods present several shortcomings which negatively impact the detection of early stage carcinogenesis, including low uptake due to patient discomfort. As a result, developing novel, non-invasive alternatives is an important research priority. Recent advancements in the field of breathomics, the study of breath composition and analysis, have paved the way for new avenues for non-invasive cancer detection and effective monitoring. Harnessing the utility of Volatile Organic Compounds in exhaled breath, breathomics has the potential to disrupt colorectal cancer screening practices. Our goal is to outline key research efforts in this area focusing on machine learning methods used for the analysis of breathomics data, highlight challenges involved in artificial intelligence application in this context, and suggest possible future directions which are currently considered within the framework of the European project ONCOSCREEN. [ABSTRACT FROM AUTHOR]

Patients with COPD are at high risk of lung cancer developing, but no validated predictive biomarkers have been reported to identify these patients. Molecular profiling of exhaled breath by electronic nose (eNose) technology may qualify for early detection of lung cancer in patients with COPD. Can eNose technology be used for prospective detection of early lung cancer in patients with COPD? BreathCloud is a real-world multicenter prospective follow-up study using diagnostic and monitoring visits in day-to-day clinical care of patients with a standardized diagnosis of asthma, COPD, or lung cancer. Breath profiles were collected at inclusion in duplicate by a metal-oxide semiconductor eNose positioned at the rear end of a pneumotachograph (SpiroNose; Breathomix). All patients with COPD were managed according to standard clinical care, and the incidence of clinically diagnosed lung cancer was prospectively monitored for 2 years. Data analysis involved advanced signal processing, ambient air correction, and statistics based on principal component (PC) analysis, linear discriminant analysis, and receiver operating characteristic analysis. Exhaled breath data from 682 patients with COPD and 211 patients with lung cancer were available. Thirty-seven patients with COPD (5.4%) demonstrated clinically manifest lung cancer within 2 years after inclusion. Principal components 1, 2, and 3 were significantly different between patients with COPD and those with lung cancer in both training and validation sets with areas under the receiver operating characteristic curve of 0.89 (95% CI, 0.83-0.95) and 0.86 (95% CI, 0.81-0.89). The same three PCs showed significant differences (P <.01) at baseline between patients with COPD who did and did not subsequently demonstrate lung cancer within 2 years, with a cross-validation value of 87% and an area under the receiver operating characteristic curve of 0.90 (95% CI, 0.84-0.95). Exhaled breath analysis by eNose identified patients with COPD in whom lung cancer became clinically manifest within 2 years after inclusion. These results show that eNose assessment may detect early stages of lung cancer in patients with COPD. [ABSTRACT FROM AUTHOR]

Key messages What is already known on this topic—Breath VOC analysis is a potential technology for PTB detection. However, it is still desirable for a real-time, robust, accurate, and simple breath analysis platform for clinical application. What this study adds—An online breath detection for PTB was proposed and demonstrated with high sensitivity and specificity in a large clinical cohort. How this study might affect research, practice, or policy—This study may promote the application of breath detection in clinical TB detection and related biomarker studies.

Exhaled breath analysis using an e-nose is a groundbreaking tool for exhaled volatile organic compound (VOC) analysis, which has already shown its applicability in several respiratory and systemic diseases. It is still unclear whether food intake can be considered a confounder when analyzing the VOC-profile. We aimed to assess whether an e-nose can discriminate exhaled breath before and after predefined food intake at different time periods. We enrolled 28 healthy non-smoking adults and collected their exhaled breath as follows: (a) before food intake, (b) within 5 min after food consumption, (c) within 1 h after eating, and (d) within 2 h after eating. Exhaled breath was collected by a formerly validated method and analyzed by an e-nose (Cyranose 320). By principal component analysis, significant variations in the exhaled VOC-profile were shown for principal component 1 (capturing 63.4% of total variance) when comparing baseline vs. 5 min and vs. 1 h after food intake (both p < 0.05). No significance was shown in the comparison between baseline and 2 h after food intake. Therefore, the exhaled VOC-profile seems to be influenced by very recent food intake. Interestingly, two hours might be sufficient to avoid food induced alterations of exhaled VOC-spectrum when sampling for research protocols. [ABSTRACT FROM AUTHOR]

Introduction: The human breath is an accurate but complex read-out of many physiological processes in the organism that can be monitored via volatile organic compounds (VOCs) in the exhaled air. However, there are many confounding variables that limit the transfer and application of breath analysis to become a clinical procedure. Method: This work aims to establish a systematic procedure for sampling and characterization of various everyday influences of healthy subjects using proton transfer reaction-mass spectrometry (PTR-MS). In order to limit the influencing factors on the breath profile, a standard analysis procedure for sampling and evaluation of the exhaled breath samples was developed. The correlations between the selected experimental conditions and the resulting VOC profiles were investigated using a non-parametric Wilcoxon rank sum test. Results: In addition to the relevant influence of methodological experimental parameters, interesting insights into the effect of everyday factors on the exhalat gas were obtained and discussed. Furthermore, subject and condition-specific differences were found in the exhaled air of male and female subjects. Conclusion: With a more robust, standardized and reproducible breath sampling protocol, breath analysis is a promising non-invasive tool towards a system-wide understanding and personalized diagnosis and treatment of a wide range of diseases.

Due to their immediate exhalation after generation at the cellular/microbiome levels, exhaled volatile organic compounds (VOCs) may provide real-time information on pathophysiological mechanisms and the host response to infection. In recent years, the metabolic profiling of the most frequent respiratory infections has gained interest as it holds potential for the early, non-invasive detection of pathogens and the monitoring of disease progression and the response to therapy. Using previously unpublished data, randomly selected individuals from a COVID-19 test center were included in the study. Based on multiplex PCR results (non-SARS-CoV-2 respiratory pathogens), the breath profiles of 479 subjects with the presence or absence of flu-like symptoms were obtained using proton-transfer-reaction time-of-flight mass spectrometry. Among 223 individuals, one respiratory pathogen was detected in 171 cases, and more than one pathogen in 52 cases. A total of 256 subjects had negative PCR test results and had no symptoms. The exhaled VOC profiles were affected by the presence of Haemophilus influenzae, Streptococcus pneumoniae, and Rhinovirus. The endogenous ketone, short-chain fatty acid, organosulfur, aldehyde, and terpene concentrations changed, but only a few compounds exhibited concentration changes above inter-individual physiological variations. Based on the VOC origins, the observed concentration changes may be attributed to oxidative stress and antioxidative defense, energy metabolism, systemic microbial immune homeostasis, and inflammation. In contrast to previous studies with pre-selected patient groups, the results of this study demonstrate the broad inter-individual variations in VOC profiles in real-life screening conditions. As no unique infection markers exist, only concentration changes clearly above the mentioned variations can be regarded as indicative of infection or colonization.

Early disease detection and diagnosis through breath-based chemical assessment is broadly studied as a non-invasive tool and used as a cutting-edge opportunity in health care. Breath analytics or Breathomics is based on the recognition of levels of metabolites such as Volatile Organic Compounds (VOCs) and inorganic gases in an exhaled human breath. Lung cancer, one such disease state, alters the concentrations of hydrocarbons released in breath due to oxidative stress and lipid pre-oxidation. Heptane can be utilized as a VOC biomarker for the non-invasive diagnosis of lung cancer. This work outlines the fabrication of a graphitic carbon nitride-based electrochemical sensor platform that possesses increased catalytic activity and can be used for the screening of heptane vapors in the range of 0.45–5 ppm limit of detection of 0.45 ppm with 95% confidence interval. The synthesized material is characterized and validated using various standard analytical methods. Chronoamperometry is employed as an electrochemical technique to examine the diffusion dynamics of the target analyte. We demonstrated the specific sensing responses of the system in the presence of interferants by executing a cross-reactivity study with respect to other commonly found interferants in breath. We effectively established the use of a graphitic carbon nitride-based electrochemical sensor for point-of-care screening (qualitative analysis with p

Background: Diagnostics for pulmonary tuberculosis (PTB) are usually inaccurate, expensive, or complicated. The breathomics-based method may be an attractive option for fast and noninvasive PTB detection. Method: Exhaled breath samples were collected from 518 PTB patients and 887 controls and tested on the real-time high-pressure photon ionization time-of-flight mass spectrometer. Machine learning algorithms were employed for breathomics analysis and PTB detection mode, whose performance was evaluated in 430 blinded clinical patients. Results: The breathomics-based PTB detection model achieved an accuracy of 92.6%, a sensitivity of 91.7%, a specificity of 93.0%, and an AUC of 0.975 in the blinded test set (n = 430). Age, sex, and anti-tuberculosis treatment does not significantly impact PTB detection performance. In distinguishing PTB from other pulmonary diseases (n = 182), the VOC modes also achieve good performance with an accuracy of 91.2%, a sensitivity of 91.7%, a specificity of 88.0%, and an AUC of 0.961. Conclusions: The simple and noninvasive breathomics-based PTB detection method was demonstrated with high sensitivity and specificity, potentially valuable for clinical PTB screening and diagnosis. Key messages: What is already known on this topic—Breath VOC analysis is a potential technology for PTB detection. However, it is still desirable for a real-time, robust, accurate, and simple breath analysis platform for clinical application. What this study adds—An online breath detection for PTB was proposed and demonstrated with high sensitivity and specificity in a large clinical cohort. How this study might affect research, practice, or policy—This study may promote the application of breath detection in clinical TB detection and related biomarker studies. [ABSTRACT FROM AUTHOR]

Cancers, chronic diseases and respiratory infections are major causes of mortality and present diagnostic and therapeutic challenges for health care. There is an unmet medical need for non-invasive, easy-to-use biomarkers for the early diagnosis, phenotyping, predicting and monitoring of the therapeutic responses of these disorders. Exhaled breath sampling is an attractive choice that has gained attention in recent years. Exhaled nitric oxide measurement used as a predictive biomarker of the response to anti-eosinophil therapy in severe asthma has paved the way for other exhaled breath biomarkers. Advances in laser and nanosensor technologies and spectrometry together with widespread use of algorithms and artificial intelligence have facilitated research on volatile organic compounds and artificial olfaction systems to develop new exhaled biomarkers. We aim to provide an overview of the recent advances in and challenges of exhaled biomarker measurements with an emphasis on the applicability of their measurement as a non-invasive, point-of-care diagnostic and monitoring tool. [ABSTRACT FROM AUTHOR]

Background: The triple combination Elexacaftor/Tezacaftor/Ivacaftor (ETI) translates into major respiratory improvements in adults; yet current clinical endpoints may prove insufficiently sensitive in young children. We hypothesised that ETI rapidly modifies the lungs' metabolism, resulting in changes in breath composition., Methods: Eleven children with CF were enrolled in a longitudinal pilot study at the paediatric Necker hospital. Breath was collected on sorbent tubes using a ReCIVA® device before, after one week and one month of ETI. Samples were analysed by 2D-gas chromatography-mass spectrometry (2D-GC-MS). A linear mixed-effect model, corrected for clinical confounding factors, identified exhaled metabolites differentially expressed throughout the visits. Correlations were calculated between these and clinical indicators., Results: Breath collection was successful in all children from six years old. They presented a decreased sweat chloride and improved lung function as early as within one week of ETI. Breath composition gradually evolved over the visits. ETI induced significant modifications in the level of 12 breath metabolites. Amongst those, dimethyl sulphide and tetradecene changes correlated with improvements in forced expiratory volume in one second (FEV 1 ) and forced expiratory flow (FEF 25-75 ), whilst 3-methyldecane and 3-(chloromethyl)-heptane were predictive of changes in lung clearance index (LCI 2.5 )., Conclusions: ETI impacts the breath profile from the first week of treatment. Not only could "breathomics" bring mechanistic insights into the metabolic impact of ETI, but it may also offer novel non-invasive options to monitor CF disease and predict therapeutic response., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Isabelle Sermet-Gaudelus reports a relationship with Vertex Pharmaceuticals Incorporated that includes: consulting or advisory, funding grants, and travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Major depressive disorder (MDD) is one of the most common psychiatric disorders with multifactorial etiologies. Metabolomics has recently emerged as a particularly potential quantitative tool that provides a multi-parametric signature specific to several mechanisms underlying the heterogeneous pathophysiology of MDD. The main purpose of the present study was to investigate possibilities and limitations of breath-based metabolomics, breathomics patterns to discriminate MDD patients from healthy controls (HCs) and identify the altered metabolic pathways in MDD. Methods: Breath samples were collected in Tedlar bags at awakening, 30 and 60 min after awakening from 26 patients with MDD and 25 HCs. The non-targeted breathomics analysis was carried out by proton transfer reaction mass spectrometry. The univariate analysis was first performed by T-test to rank potential biomarkers. The metabolomic pathway analysis and hierarchical clustering analysis (HCA) were performed to group the significant metabolites involved in the same metabolic pathways or networks. Moreover, a support vector machine (SVM) predictive model was built to identify the potential metabolites in the altered pathways and clusters. The accuracy of the SVM model was evaluated by receiver operating characteristics (ROC) analysis. Results: A total of 23 differential exhaled breath metabolites were significantly altered in patients with MDD compared with HCs and mapped in five significant metabolic pathways including aminoacyl-tRNA biosynthesis (p = 0.0055), branched chain amino acids valine, leucine and isoleucine biosynthesis (p = 0.0060), glycolysis and gluconeogenesis (p = 0.0067), nicotinate and nicotinamide metabolism (p = 0.0213) and pyruvate metabolism (p = 0.0440). Moreover, the SVM predictive model showed that butylamine (p = 0.0005, pFDR=0.0006), 3-methylpyridine (p = 0.0002, pFDR = 0.0012), endogenous aliphatic ethanol isotope (p = 0.0073, pFDR = 0.0174), valeric acid (p = 0.005, pFDR = 0.0162) and isoprene (p = 0.038, pFDR = 0.045) were potential metabolites within identified clusters with HCA and altered pathways, and discriminated between patients with MDD and non-depressed ones with high sensitivity (0.88), specificity (0.96) and area under curve of ROC (0.96). Conclusion: According to the results of this study, the non-targeted breathomics analysis with high-throughput sensitive analytical technologies coupled to advanced computational tools approaches offer completely new insights into peripheral biochemical changes in MDD. [ABSTRACT FROM AUTHOR]

The measurement of exhaled volatile organic compounds (VOCs) in exhaled breath (breathomics) represents an exciting biomarker matrix for airways disease, with early research indicating a sensitivity to airway inflammation. One of the key aspects to analytical validity for any clinical biomarker is an understanding of the short-term repeatability of measures. We collected exhaled breath samples on 5 consecutive days in 14 subjects with severe asthma who had undergone extensive clinical characterisation. Principal component analysis on VOC abundance across all breath samples revealed no variance due to the day of sampling. Samples from the same patients clustered together and there was some separation according to T2 inflammatory markers. The intra-subject and between-subject variability of each VOC was calculated across the 70 samples and identified 30.35% of VOCs to be erratic: variable between subjects but also variable in the same subject. Exclusion of these erratic VOCs from machine learning approaches revealed no apparent loss of structure to the underlying data or loss of relationship with salient clinical characteristics. Moreover, cluster evaluation by the silhouette coefficient indicates more distinct clustering. We are able to describe the short-term repeatability of breath samples in a severe asthma population and corroborate its sensitivity to airway inflammation. We also describe a novel variance-based feature selection tool that, when applied to larger clinical studies, could improve machine learning model predictions. [ABSTRACT FROM AUTHOR]

BackgroundMajor depressive disorder (MDD) is one of the most common psychiatric disorders with multifactorial etiologies. Metabolomics has recently emerged as a particularly potential quantitative tool that provides a multi-parametric signature specific to several mechanisms underlying the heterogeneous pathophysiology of MDD. The main purpose of the present study was to investigate possibilities and limitations of breath-based metabolomics, breathomics patterns to discriminate MDD patients from healthy controls (HCs) and identify the altered metabolic pathways in MDD.MethodsBreath samples were collected in Tedlar bags at awakening, 30 and 60 min after awakening from 26 patients with MDD and 25 HCs. The non-targeted breathomics analysis was carried out by proton transfer reaction mass spectrometry. The univariate analysis was first performed by T-test to rank potential biomarkers. The metabolomic pathway analysis and hierarchical clustering analysis (HCA) were performed to group the significant metabolites involved in the same metabolic pathways or networks. Moreover, a support vector machine (SVM) predictive model was built to identify the potential metabolites in the altered pathways and clusters. The accuracy of the SVM model was evaluated by receiver operating characteristics (ROC) analysis.ResultsA total of 23 differential exhaled breath metabolites were significantly altered in patients with MDD compared with HCs and mapped in five significant metabolic pathways including aminoacyl-tRNA biosynthesis (p = 0.0055), branched chain amino acids valine, leucine and isoleucine biosynthesis (p = 0.0060), glycolysis and gluconeogenesis (p = 0.0067), nicotinate and nicotinamide metabolism (p = 0.0213) and pyruvate metabolism (p = 0.0440). Moreover, the SVM predictive model showed that butylamine (p = 0.0005, pFDR=0.0006), 3-methylpyridine (p = 0.0002, pFDR = 0.0012), endogenous aliphatic ethanol isotope (p = 0.0073, pFDR = 0.0174), valeric acid (p = 0.005, pFDR = 0.0162) and isoprene (p = 0.038, pFDR = 0.045) were potential metabolites within identified clusters with HCA and altered pathways, and discriminated between patients with MDD and non-depressed ones with high sensitivity (0.88), specificity (0.96) and area under curve of ROC (0.96).ConclusionAccording to the results of this study, the non-targeted breathomics analysis with high-throughput sensitive analytical technologies coupled to advanced computational tools approaches offer completely new insights into peripheral biochemical changes in MDD.

The remarkable potential of breath analysis in medical care and diagnosis, and the consequent development of electronic noses, is currently attracting the interest of the research community. This is mainly due to the possibility of applying the technique for early diagnosis, screening campaigns, or tracking the effectiveness of treatment. Carbon nanotubes (CNTs) are known to be good candidates for gas sensing, and they have been recently considered for the development of electronic noses. The present work has the aim of reviewing the available literature on the development of CNTs-based electronic noses for breath analysis applications, detailing the functionalization procedure used to prepare the sensors, the breath sampling techniques, the statistical analysis methods, the diseases under investigation, and the population studied. The review is divided in two main sections: one focusing on the e-noses completely based on CNTs and one reporting on the e-noses that feature sensors based on CNTs, along with sensors based on other materials. Finally, a classification is presented among studies that report on the e-nose capability to discriminate biomarkers, simulated breath, and animal or human breath. [ABSTRACT FROM AUTHOR]

Abstract Background Data handling in clinical bioinformatics is often inadequate. No freely available tools provide straightforward approaches for consistent, flexible metadata collection and linkage of related experimental data generated locally by vendor software. Results To address this problem, we created LabPipe, a flexible toolkit which is driven through a local client that runs alongside vendor software and connects to a light-weight server. The toolkit allows re-usable configurations to be defined for experiment metadata and local data collection, and handles metadata entry and linkage of data. LabPipe was piloted in a multi-site clinical breathomics study. Conclusions LabPipe provided a consistent, controlled approach for handling metadata and experimental data collection, collation and linkage in the exemplar study and was flexible enough to deal effectively with different data handling challenges.

Summary: Background: Breathomics testing has been considered a promising method for detection and screening for lung cancer. This study aimed to identify breath biomarkers of lung cancer through perioperative dynamic breathomics testing. Methods: The discovery study was prospectively conducted between Sept 1, 2020 and Dec 31, 2020 in Peking University People's Hospital in China. High-pressure photon ionisation time-of-flight mass spectrometry was used for breathomics testing before surgery and 4 weeks after surgery. 28 volatile organic compounds (VOCs) were selected as candidates based on a literature review. VOCs that changed significantly postoperatively in patients with lung cancer were selected as potential breath biomarkers. An external validation was conducted to evaluate the performance of these VOCs for lung cancer diagnosis. Multivariable logistic regression was used to establish diagnostic models based on selected VOCs. Findings: In the discovery study of 84 patients with lung cancer, perioperative breathomics demonstrated 16 VOCs as lung cancer breath biomarkers. They were classified as aldehydes, hydrocarbons, ketones, carboxylic acids, and furan. In the external validation study including 157 patients with lung cancer and 368 healthy individuals, patients with lung cancer showed elevated spectrum peak intensity of the 16 VOCs after adjusting for age, sex, smoking, and comorbidities. The diagnostic model including 16 VOCs achieved an area under the curve (AUC) of 0.952, sensitivity of 89.2%, specificity of 89.1%, and accuracy of 89.1% in lung cancer diagnosis. The diagnostic model including the top eight VOCs achieved an AUC of 0.931, sensitivity of 86.0%, specificity of 87.2%, and accuracy of 86.9%. Interpretation: Perioperative dynamic breathomics is an effective approach for identifying lung cancer breath biomarkers. 16 lung cancer-related breath VOCs (aldehydes, hydrocarbons, ketones, carboxylic acids, and furan) were identified and validated. Further studies are warranted to investigate the underlying mechanisms of identified VOCs. Funding: National Natural Science Foundation of China (82173386) and Peking University People's Hospital Scientific Research Development Founds (RDH2021–07).

The prevalence of patients with bronchiectasis (BE) has been rising in recent years, which increases the substantial burden on the family and society. Exploring a convenient, effective, and low-cost screening tool for the diagnosis of BE is urgent. We expect to identify the accuracy (ACC) of breath biomarkers (BBs) for the diagnosis of BE through breathomics testing and explore the association between BBs and clinical features of BE. Exhaled breath samples were collected and detected by high-pressure photon ionization time-of-flight mass spectrometry in a cross-sectional study. Exhaled breath samples were from 215 patients with BE and 295 control individuals. The potential BBs were selected via the machine learning (ML) method. The overall performance was assessed for the BBs-based BE detection model. The significant BBs between different subgroups such as the severity of BE, acute or stable stage, combined with hemoptysis or not, with or without nontuberculous mycobacterium (NTM), P. aeruginosa ( P.a ) isolation or not, and the BBs related to the number of involved lung lobes and lung function were discovered and analyzed. The top ten BBs based ML model achieved an area under the curve of 0.940, sensitivity of 90.7%, specificity of 85%, and ACC of 87.4% in BE diagnosis. Except for the top ten BBs, other BBs were found also related to the severity, acute/stable status, hemoptysis or not, NTM infection, P.a isolation, the number of involved lobes, and three lung functional parameters in BE patients. BBs-based BE detection model showed good ACC for diagnosis. BBs have a close relationship with the clinical features of BE. The breath test method may provide a new strategy for BE screening and personalized management., (Creative Commons Attribution license.)

Microbial odors, produced by bacteria and fungi, play a significant role in our environment and can be useful in diagnosing infectious diseases. These odors are mediated by volatile organic compounds (VOCs) and can be detected through various methods such as gas chromatography/mass spectrometry and electronic nose technology. Detecting infections through scent has already been successful with the help of animals like rats and dogs, as well as through breath tests. Pathogenic microbes release VOCs to influence their hosts and enhance their own transmission. Understanding and utilizing these microbial odors could lead to new opportunities for improving human health. [Extracted from the article]

In this study, exhaled breath testing has been considered a promising method for the detection and monitoring of breast cancer (BC). A high-pressure photon ionization time-of-flight mass spectrometry (HPPI-TOFMS) platform was used to detect volatile organic compounds (VOCs) in breath samples. Then, machine learning (ML) models were constructed on VOCs for the diagnosis of BC and its progression monitoring. Ultimately, 1981 women with useable breath samples were included in the study, of whom 937 (47.3 %) had been diagnosed with BC. VOC panels were used for ML model construction for BC detection and progression monitoring. On the blinded testing cohort, this VOC-based model successfully differentiated patients with and without BC with sensitivity, specificity, and area under receiver operator characteristic curve (AUC) values of 85.9 %, 90.4 %, and 0.946. The corresponding AUC values when differentiating between patients with and without lymph node metastasis (LNM) or between patients with tumor-node-metastasis (TNM) stage 0/I/II or III/IV disease were 0.840 and 0.708, respectively. While developed VOC-based models exhibited poor performance when attempting to differentiate between patients based on pathological patterns (Ductal carcinoma in situ (DCIS) vs Invasive BC (IBC)) or molecular subtypes (Luminal vs Human epidermal growth factor receptor 2 (HER2+) vs Triple-negative BC (TNBC)) of BC. Collectively, the HPPI-TOFMS-based breathomics approaches may offer value for the detection and progression monitoring of BC. Additional research is necessary to explore the fundamental mechanisms of the identified VOCs. [Display omitted] • Our study findings highlight a novel breast cancer detection and monitoring strategy. • HPPI-TOFMS-based breathomics approaches may offer value for the detection and progression monitoring of breast cancer. • Significant differences in the VOC profiles of breast cancer patients were detected relative to those in non-cancer patients. [ABSTRACT FROM AUTHOR]

Abstract Background There is no definitive method of accurately diagnosing appendicitis before surgery. We evaluated the feasibility of collecting breath samples in children with abdominal pain and gathered preliminary data on the accuracy of breath tests. Methods We conducted a prospective pilot study at a large tertiary referral paediatric hospital in the UK. We recruited 50 participants with suspected appendicitis, aged between 5 and 15 years. Five had primary diagnosis of appendicitis. The primary outcome was the number of breath samples collected. We also measured the number of samples processed within 2 h and had CO2 ≥ 3.5%. Usability was assessed by patient-reported pain pre- and post-sampling and user-reported sampling difficulty. Logistic regression analysis was used to predict appendicitis and evaluated using the area under the receiver operator characteristic curve (AUROC). Results Samples were collected from all participants. Of the 45 samples, 36 were processed within 2 h. Of the 49 samples, 19 had %CO2 ≥ 3.5%. No difference in patient-reported pain was observed (p = 0.24). Sampling difficulty was associated with patient age (p = 0.004). The logistic regression model had AUROC = 0.86. Conclusions Breath tests are feasible and acceptable to patients presenting with abdominal pain in clinical settings. We demonstrated adequate data collection with no evidence of harm to patients. The AUROC was better than a random classifier; more specific sensors are likely to improve diagnostic performance. Trial registration ClinicalTrials.gov, NCT03248102. Registered 14 Aug 2017.

Background: Assessing biomarker profiles in various body fluids is of large value to discern between the sole use of nicotine products. In particular, the assessment of the product compliance is required for long-term clinical studies. The objective of this study was the identification of biomarkers and biomarker patterns in body fluids, to distinguish between combustibles, heated tobacco products, electronic cigarettes, oral tobacco and oral/dermal nicotine products used for nicotine replacement therapy (NRT), as well as a control group of non-users. Methods: A controlled, single-center study was conducted with 60 healthy subjects, divided into 6 groups (5 nicotine product user groups and one non-user group) based on their sole use of the products of choice. The subjects were confined for 76 h, during which, free and uncontrolled use of the products was provided. Sample collections were performed according to the study time schedule provided in Table 2. The primary outcome will be validated through analysis of the collected biospecimens (urine, blood, saliva, exhaled breath and exhaled breath condensate) by means of untargeted omics approaches (i.e. exposomics, breathomics and adductomics). Secondary outcome will include established biomarker quantification methods to allow for the identification of typical biomarker patterns. Statistical analysis tools will be used to specifically discriminate different product use categories. Results/Conclusions: The clinical trial was successfully completed in May 2020, resulting in sample management and preparations for the quantitative and qualitative analyses. This work will serve as a solid basis to discern between biomarker profiles of different nicotine product user groups. The knowledge collected during this research will be required to develop prototype diagnostic tools that can reliably assess the differences and evaluate possible health risks of various nicotine products.

Derzeit basieren die Diagnose von Exazerbationen bei Mukoviszidose-Patienten und die Überwachung der Krankheitsaktivität hauptsächlich auf klinischen Merkmalen und Lungenfunktionstests. Eine Atemgasanalyse könnte die Diagnostik unterstützen, da bestimmte Muster von flüchtigen organischen Verbindungen auf Mukoviszidose-assoziierte bakterielle Infektionen hinweisen und auch eine Früherkennung einer Mukoviszidose-Exazerbation ermöglichen. [ABSTRACT FROM AUTHOR]

Lung cancer remains a global health concern, demanding the development of noninvasive, prompt, selective, and point-of-care diagnostic tools. Correspondingly, breath analysis using nanobiosensors has emerged as a promising noninvasive nose-on-chip technique for the early detection of lung cancer through monitoring diversified biomarkers such as volatile organic compounds/gases in exhaled breath. This comprehensive review summarizes the state-of-the-art breath-based lung cancer diagnosis employing chemiresistive-module nanobiosensors supported by theoretical findings. It unveils the fundamental mechanisms and biological basis of breath biomarker generation associated with lung cancer, technological advancements, and clinical implementation of nanobiosensor-based breath analysis. It explores the merits, challenges, and potential alternate solutions in implementing these nanobiosensors in clinical settings, including standardization, biocompatibility/toxicity analysis, green and sustainable technologies, life-cycle assessment, and scheming regulatory modalities. It highlights nanobiosensors' role in facilitating precise, real-time, and on-site detection of lung cancer through breath analysis, leading to improved patient outcomes, enhanced clinical management, and remote personalized monitoring. Additionally, integrating these biosensors with artificial intelligence, machine learning, Internet-of-things, bioinformatics, and omics technologies is discussed, providing insights into the prospects of intelligent nose-on-chip lung cancer sniffing nanobiosensors. Overall, this review consolidates knowledge on breathomic biosensor-based lung cancer screening, shedding light on its significance and potential applications in advancing state-of-the-art medical diagnostics to reduce the burden on hospitals and save human lives.

Chronic obstructive pulmonary disease (COPD) and asthma are the most common chronic respiratory diseases. In middle-aged and elderly patients, it is difficult to distinguish between COPD and asthma based on clinical symptoms and pulmonary function examinations in clinical practice. Thus, an accurate and reliable inspection method is required. In this study, we aimed to identify breath biomarkers and evaluate the accuracy of breathomics-based methods for discriminating between COPD and asthma. In this multi-center cross-sectional study, exhaled breath samples were collected from 89 patients with COPD and 73 with asthma and detected on a high-pressure photon ionization time-of-flight mass spectrometry (HPPI-TOFMS) platform from 20 October 2022, to 20 May 2023, in four hospitals. Data analysis was performed from 15 June 2023 to 16 August 2023. The sensitivity, specificity, and accuracy were calculated to assess the overall performance of the volatile organic component (VOC)-based COPD and asthma discrimination models. Potential VOC markers related to COPD and asthma were also analyzed. The age of all participants ranged from to 18-86 years, and 54 (33.3%) were men. The age [median (minimum, maximum)] of COPD and asthma participants were 66.0 (46.0, 86.0), and 44.0 (17.0, 80.0). The male and female ratio of COPD and asthma participants were 14/75 and 40/33, respectively. Based on breathomics feature selection, ten VOCs were identified as COPD and asthma discrimination biomarkers via breath testing. The joint panel of these ten VOCs achieved an area under the curve of 0.843, sensitivity of 75.9%, specificity of 87.5%, and accuracy of 80.0% in COPD and asthma discrimination. Furthermore, the VOCs detected in the breath samples were closely related to the clinical characteristics of COPD and asthma. The VOC-based COPD and asthma discrimination model showed good accuracy, providing a new strategy for clinical diagnosis. Breathomics-based methods may play an important role in the diagnosis of COPD and asthma., (Creative Commons Attribution license.)

(1) Background: An electronic nose applies a sensor array to detect volatile biomarkers in exhaled breath to diagnose diseases. The overall diagnostic accuracy remains unknown. The objective of this review was to provide an estimate of the diagnostic accuracy of sensor-based breath tests for the diagnosis of diseases. (2) Methods: We searched the PubMed and Web of Science databases for studies published between 1 January 2010 and 14 October 2021. The search was limited to human studies published in the English language. Clinical trials were not included in this review. (3) Results: Of the 2418 records identified, 44 publications were eligible, and 5728 patients were included in the final analyses. The pooled sensitivity was 90.0% (95% CI, 86.3–92.8%, I2 = 47.7%), the specificity was 88.4% (95% CI, 87.1–89.5%, I2 = 81.4%), and the pooled area under the curve was 0.93 (95% CI 0.91–0.95). (4) Conclusion: The findings of our review suggest that a standardized report of diagnostic accuracy and a report of the accuracy in a test set are needed. Sensor array systems of electronic noses have the potential for noninvasiveness at the point-of-care in hospitals. Nevertheless, the procedure for reporting the accuracy of a diagnostic test must be standardized.

Abstract Background Lipid peroxidation plays an important role in the pathogenesis of pneumoconiosis. Volatile organic compounds (VOCs) generated from lipid peroxidation might be used to detect pneumoconiosis. The objective of this study was to develop a breath test for pneumoconiosis. Methods A case-control study was designed. Breath and ambient air were analysed by gas chromatography/mass spectrometry. After blank correction to prevent contamination from ambient air, we used canonical discriminant analysis (CDA) to assess the discrimination accuracy and principal component analysis (PCA) to generate a prediction score. The prediction accuracy was calculated and validated using the International Classification of Radiographs of the Pneumoconiosis criteria combined with an abnormal pulmonary function test as a reference standard. We generated a receiver operator characteristic (ROC) curve and calculated the area under the ROC curve (AUC) to estimate the screening accuracy of the breath test. Results We enrolled 200 stone workers. After excluding 5 subjects with asthma and 16 subjects who took steroids or nonsteroidal anti-inflammatory drugs, a total of 179 subjects were used in the final analyses, which included 25 cases and 154 controls. By CDA, 88.8% of subjects were correctly discriminated by their exposure status and the presence of pneumoconiosis. After excluding the VOCs of automobile exhaust and cigarette smoking, pentane and C5-C7 methylated alkanes constituted the major VOCs in the breath of persons with pneumoconiosis. Using the prediction score generated from PCA, the ROC-AUC was 0.88 (95% CI = 0.80—0.95), and the mean ROC-AUC of 5-fold cross-validation was 0.90. The breath test had good accuracy for pneumoconiosis diagnosis. Conclusion The analysis of breath VOCs has potential in the screening of pneumoconiosis for its non-invasiveness and high accuracy. We suggest that a multi-centre study is warranted and that all procedures must be standardized before clinical application.

Chlorine‐based disinfectants protect pool water from pathogen contamination but produce potentially harmful halogenated disinfection by‐products (DBPs). This study characterized the bioaccumulation and elimination of exhaled DBPs post‐swimming and investigated changes in exhaled breath profiles associated with chlorinated pool exposure. Nineteen participants provided alveolar‐enriched breath samples prior to and 5, 90, 300, 510, and 600 minutes post‐swimming. Known DBPs associated with chlorinated water were quantitated by thermal desorption‐gas chromatography‐mass spectrometry. Two distinct exhaled DBP elimination profiles were observed. Most participants (84%) reported peak concentrations immediately post‐swimming that reduced exponentially. A sub‐group exhibited a previously unobserved and delayed washout profile with peak levels at 90 minutes post‐exposure. Metabolomic investigations tentatively identified two candidate biomarkers associated with swimming pool exposure, demonstrating an upregulation in the hours after exposure. These data demonstrated a hitherto undescribed exhaled DBP elimination profile in a small number of participants which contrasts previous findings of uniform accumulation and exponential elimination. This sub‐group which exhibited delayed peak‐exhaled concentrations suggests the uptake, processing, and immediate elimination of DBPs are not ubiquitous across individuals as previously understood. Additionally, non‐targeted metabolomics highlighted extended buildup of compounds tentatively associated with swimming in a chlorinated pool environment that may indicate airway responses to DBP exposure. [ABSTRACT FROM AUTHOR]

Breathomics is an emerging field that aims to non-invasively diagnose and monitor respiratory diseases using the analysis of exhaled breath. In this review, we present a summary of the various analytical methods such as gas chromatography, and mass spectrometry that are used for the characterization of these VOCs and inorganic gases. We further elucidate on electrochemical transduction mechanism for ultrasensitive characterization of respiratory diseases in breathomics. Electrochemical sensors have several advantages over other detection methods, including high sensitivity, selectivity, and low cost. Electrochemical sensors can be miniaturized and integrated into portable devices, allowing for point-of-care diagnosis. Further advancements in sampling techniques, statistical analysis, and technology integration could pave the way for the widespread use of breath analysis in clinical practice. As research in breathomics continues to advance, electrochemical sensors are likely to play an increasingly significant part in the diagnosis and treatment of respiratory diseases. [Display omitted] • Breathomics is a powerful tool, widely being investigated for logitudal health monitoring • Breathomics provides mechanistic insights on the levels of endogeneously produced volatile organic compounds (VOCs). • Standard analytical methods , that are used for characterisation of VOCs and gases. • Overview of electrochemical transduction mechanism for breathomics screening. • Challenges and prospects for understanding and critically evaluating the scope of this field are also presented. [ABSTRACT FROM AUTHOR]

Background: “breathomics” enables indirect analysis of metabolic patterns underlying a respiratory disease. In this study, we analyze exhaled breath condensate (EBC) in asthmatic children before (T0) and after (T1) a three-week course of inhaled beclomethasone dipropionate (BDP). Methods: we recruited steroid-naive asthmatic children for whom inhaled steroids were indicated and healthy children, evaluating asthma control, spirometry and EBC (in asthmatics at T0 and T1). A liquid-chromatography–mass-spectrometry untargeted analysis was applied to EBC and a mass spectrometry-based target analysis to urine samples. Results: metabolomic analysis discriminated asthmatic (n = 26) from healthy children (n = 16) at T0 and T1, discovering 108 and 65 features relevant for the discrimination, respectively. Searching metabolomics databases, seven putative biomarkers with a plausible role in asthma biochemical–metabolic processes were found. After BDP treatment, asthmatic children, in the face of an improved asthma control (p < 0.001) and lung function (p = 0.01), showed neither changes in EBC metabolomic profile nor in urinary endogenous steroid profile. Conclusions: “breathomics” can discriminate asthmatic from healthy children, with prostaglandin, fatty acid and glycerophospholipid as putative markers. The three-week course of BDP—in spite of a significant clinical improvement—was not associated with changes in EBC metabolic arrangement and urinary steroid profile.

The breathomics approach to express-diagnosis of bronchopulmonary diseases based on spectral analysis of volatile organic compounds in a patient’s exhaled air is discussed. The basic demands and possible technical solutions to laser photoacoustic spectroscopy equipment in a framework of breathomics are presented. An example of differential diagnostics of the set of bronchopulmonary diseases, including lung cancer (LC) patients (N = 9); patients with chronic obstructive pulmonary disease (COPD) (N = 12); patients with pneumonia (N = 11) and a control group of healthy volunteers using breath air analysis by laser photoacoustic spectroscopy and machine learning is presented.

Background: Prospective pharmacological studies on breathomics profiles in COPD patients have not been previously reported. We assessed the effects of treatment and withdrawal of an extrafine inhaled corticosteroid (ICS)-long-acting β2-agonist (LABA) fixed dose combination (FDC) using a multidimensional classification model including breathomics.Methods: A pilot, proof-of-concept, pharmacological study was undertaken in 14 COPD patients on maintenance treatment with inhaled fluticasone propionate/salmeterol (500/50 μg b.i.d.) for at least 8 weeks (visit 1). Patients received 2-week treatment with inhaled beclomethasone dipropionate/formoterol (100/6 μg b.i.d.) (visit 2), 4-week treatment with formoterol alone (6 μg b.i.d.) (visit 3), and 4-week treatment with beclomethasone/formoterol (100/6 μg b.i.d.) (visit 4). Exhaled breath analysis with two e-noses, based on different technologies, and exhaled breath condensate (EBC) NMR-based metabolomics were performed. Sputum cell counts, sputum supernatant and EBC prostaglandin E2 (PGE2) and 15-F2t-isoprostane, fraction of exhaled nitric oxide, and spirometry were measured.Results: Compared with formoterol alone, EBC acetate and sputum PGE2, reflecting airway inflammation, were reduced after 4-week beclomethasone/formoterol. Three independent breathomics techniques showed that extrafine beclomethasone/formoterol short-term treatment was associated with different breathprints compared with regular fluticasone propionate/salmeterol. Either ICS/LABA FDC vs. formoterol alone was associated with increased pre-bronchodilator FEF25−75% and FEV1/FVC (P = 0.008–0.029). The multidimensional model distinguished fluticasone propionate/salmeterol vs. beclomethasone/formoterol, fluticasone propionate/salmeterol vs. formoterol, and formoterol vs. beclomethasone/formoterol (accuracy > 70%, P < 0.01).Conclusions: Breathomics could be used for assessing ICS treatment and withdrawal in COPD patients. Large, controlled, prospective pharmacological trials are required to clarify the biological implications of breathomics changes. EUDRACT number: 2012-001749-42.

Computational breath analysis is a growing research area aiming at identifying volatile organic compounds (VOCs) in human breath to assist medical diagnostics of the next generation. While inexpensive and non-invasive bioanalytical technologies for metabolite detection in exhaled air and bacterial/fungal vapor exist and the first studies on the power of supervised machine learning methods for profiling of the resulting data were conducted, we lack methods to extract hidden data features emerging from confounding factors. Here, we present Carotta, a new cluster analysis framework dedicated to uncovering such hidden substructures by sophisticated unsupervised statistical learning methods. We study the power of transitivity clustering and hierarchical clustering to identify groups of VOCs with similar expression behavior over most patient breath samples and/or groups of patients with a similar VOC intensity pattern. This enables the discovery of dependencies between metabolites. On the one hand, this allows us to eliminate the effect of potential confounding factors hindering disease classification, such as smoking. On the other hand, we may also identify VOCs associated with disease subtypes or concomitant diseases. Carotta is an open source software with an intuitive graphical user interface promoting data handling, analysis and visualization. The back-end is designed to be modular, allowing for easy extensions with plugins in the future, such as new clustering methods and statistics. It does not require much prior knowledge or technical skills to operate. We demonstrate its power and applicability by means of one artificial dataset. We also apply Carotta exemplarily to a real-world example dataset on chronic obstructive pulmonary disease (COPD). While the artificial data are utilized as a proof of concept, we will demonstrate how Carotta finds candidate markers in our real dataset associated with confounders rather than the primary disease (COPD) and bronchial carcinoma (BC). Carotta is publicly available at http://carotta.compbio.sdu.dk [1].

Background: Prospective pharmacological studies on breathomics profiles in COPD patients have not been previously reported. We assessed the effects of treatment and withdrawal of an extrafine inhaled corticosteroid (ICS)-long-acting β2-agonist (LABA) fixed dose combination (FDC) using a multidimensional classification model including breathomics. Methods: A pilot, proof-of-concept, pharmacological study was undertaken in 14 COPD patients on maintenance treatment with inhaled fluticasone propionate/salmeterol (500/50 µg b.i.d.) for at least 8 weeks (visit 1). Patients received 2-week treatment with inhaled beclomethasone dipropionate/formoterol (100/6 µg b.i.d.) (visit 2), 4-week treatment with formoterol alone (6 µg b.i.d.) (visit 3), and 4-week treatment with beclomethasone/formoterol (100/6 µg b.i.d.) (visit 4). Exhaled breath analysis with two e-noses, based on different technologies, and exhaled breath condensate (EBC) NMR-based metabolomics were performed. Sputum cell counts, sputum supernatant and EBC prostaglandin E2 (PGE2) and 15-F2t-isoprostane, fraction of exhaled nitric oxide, and spirometry were measured. Results: Compared with formoterol alone, EBC acetate and sputum PGE2, reflecting airway inflammation, were reduced after 4-week beclomethasone/formoterol. Three independent breathomics techniques showed that extrafine beclomethasone/formoterol short-term treatment was associated with different breathprints compared with regular fluticasone propionate/salmeterol. Either ICS/LABA FDC vs. formoterol alone was associated with increased pre-bronchodilator FEF25-75% and FEV1/FVC (P = 0.008-0.029). The multidimensional model distinguished fluticasone propionate/salmeterol vs. beclomethasone/formoterol, fluticasone propionate/salmeterol vs. formoterol, and formoterol vs. beclomethasone/formoterol (accuracy > 70%, P < 0.01). Conclusions: Breathomics could be used for assessing ICS treatment and withdrawal in COPD patients. Large, controlled, prospective pharmacological trials are required to clarify the biological implications of breathomics changes. EUDRACT number: 2012-001749-42 [ABSTRACT FROM AUTHOR]

We hypothesize that oxidative stress induced by trichloramine exposure during swimming could be related to etiopathogenesis of asthma among elite swimmers. Aim To investigate the effect of a swimming training session on oxidative stress markers of asthmatic compared to non-asthmatic elite swimmers using exhaled breath ( EB) metabolomics. Methods Elite swimmers annually screened in our department (n=27) were invited and those who agreed to participate (n=20, of which 9 with asthma) had EB collected (Tedlar® bags) before and after a swimming training session. SPME fiber ( DVB/ CAR/ PDMS) was used to extract EB metabolites followed by a multidimensional gas chromatography analysis ( GC× GC-To FMS). Dataset comprises eight metabolites end products of lipid peroxidation: five aliphatic alkanes (nonane, 2,2,4,6,6-pentamethylheptane, decane, dodecane, and tetradecane) and three aldehydes (nonanal, decanal, and dodecanal). To assess exercise impact on lipid peroxidation markers, data were analyzed using principle component analysis ( PCA), which was run on the original data set and on the data set constructed using differences in the metabolite total areas before and after exercise session. Results Heatmap representation revealed that metabolites content decreased after exercise, both for control and asthma groups; however, the greater decrease was observed for controls. Asthmatics and controls did not form separated clusters; however, control swimmers demonstrated a more varied response to the exercise being dispersed along all score plot. Conclusion In well-trained athletes, swimming is associated with a decrease in oxidative stress markers independently of the presence of asthma, although a more pronounced decrease was seen in controls. [ABSTRACT FROM AUTHOR]

Asthma, chronic obstructive pulmonary disease (COPD) and asthma-COPD overlap are the third leading cause of mortality around the world. They share some common features, which can lead to misdiagnosis. To properly manage these conditions, reliable markers for early and accurate diagnosis are needed. Over the past 20 years, many molecules have been investigated in the exhaled breath condensate to better understand inflammation pathways and mechanisms related to these disorders. Recently, more advanced techniques, such as sensitive metabolomic and proteomic profiling, have been used to obtain a more comprehensive understanding. This article reviews the use of targeted and untargeted metabolomic methodology to study asthma, COPD and asthma-COPD overlap.