Exhaled volatile organic compounds in patients with non-small cell lung cancer: cross sectional and nested short-term follow-up study

BACKGROUND: Non-invasive diagnostic strategies aimed at identifying biomarkers of lung cancer are of great interest for early cancer detection. The aim of this study was to set up a new method for identifying and quantifying volatile organic compounds (VOCs) in exhaled air of patients with non-small cells lung cancer (NSCLC), by comparing the levels with those obtained from healthy smokers and non-smokers, and patients with chronic obstructive pulmonary disease. The VOC collection and analyses were repeated three weeks after the NSCLC patients underwent lung surgery. METHODS: The subjects' breath was collected in a Teflon(® )bulb that traps the last portion of single slow vital capacity. The 13 VOCs selected for this study were concentrated using a solid phase microextraction technique and subsequently analysed by means of gas cromatography/mass spectrometry. RESULTS: The levels of the selected VOCs ranged from 10(-12 )M for styrene to 10(-9 )M for isoprene. None of VOCs alone discriminated the study groups, and so it was not possible to identify one single chemical compound as a specific lung cancer biomarker. However, multinomial logistic regression analysis showed that VOC profile can correctly classify about 80 % of cases. Only isoprene and decane levels significantly decreased after surgery. CONCLUSION: As the combination of the 13 VOCs allowed the correct classification of the cases into groups, together with conventional diagnostic approaches, VOC analysis could be used as a complementary test for the early diagnosis of lung cancer. Its possible use in the follow-up of operated patients cannot be recommended on the basis of the results of our short-term nested study

A mathematical model for breath gas analysis of volatile organic compounds with special emphasis on acetone

Recommended standardized procedures for determining exhaled lower respiratory nitric oxide and nasal nitric oxide have been developed by task forces of the European Respiratory Society and the American Thoracic Society. These recommendations have paved the way for the measurement of nitric oxide to become a diagnostic tool for specific clinical applications. It would be desirable to develop similar guidelines for the sampling of other trace gases in exhaled breath, especially volatile organic compounds (VOCs) which reflect ongoing metabolism. The concentrations of water-soluble, blood-borne substances in exhaled breath are influenced by: (i) breathing patterns affecting gas exchange in the conducting airways; (ii) the concentrations in the tracheo-bronchial lining fluid; (iii) the alveolar and systemic concentrations of the compound. The classical Farhi equation takes only the alveolar concentrations into account. Real-time measurements of acetone in end-tidal breath under an ergometer challenge show characteristics which cannot be explained within the Farhi setting. Here we develop a compartment model that reliably captures these profiles and is capable of relating breath to the systemic concentrations of acetone. By comparison with experimental data it is inferred that the major part of variability in breath acetone concentrations (e.g., in response to moderate exercise or altered breathing patterns) can be attributed to airway gas exchange, with minimal changes of the underlying blood and tissue concentrations. Moreover, it is deduced that measured end-tidal breath concentrations of acetone determined during resting conditions and free breathing will be rather poor indicators for endogenous levels. Particularly, the current formulation includes the classical Farhi and the Scheid series inhomogeneity model as special limiting cases.Comment: 38 page

Isoprene and acetone concentration profiles during exercise on an ergometer

A real-time recording setup combining exhaled breath VOC measurements by proton transfer reaction mass spectrometry (PTR-MS) with hemodynamic and respiratory data is presented. Continuous automatic sampling of exhaled breath is implemented on the basis of measured respiratory flow: a flow-controlled shutter mechanism guarantees that only end-tidal exhalation segments are drawn into the mass spectrometer for analysis. Exhaled breath concentration profiles of two prototypic compounds, isoprene and acetone, during several exercise regimes were acquired, reaffirming and complementing earlier experimental findings regarding the dynamic response of these compounds reported by Senthilmohan et al. [1] and Karl et al. [2]. While isoprene tends to react very sensitively to changes in pulmonary ventilation and perfusion due to its lipophilic behavior and low Henry constant, hydrophilic acetone shows a rather stable behavior. Characteristic (median) values for breath isoprene concentration and molar flow, i.e., the amount of isoprene exhaled per minute are 100 ppb and 29 nmol/min, respectively, with some intra-individual day-to-day variation. At the onset of exercise breath isoprene concentration increases drastically, usually by a factor of ~3-4 within about one minute. Due to a simultaneous increase in ventilation, the associated rise in molar flow is even more pronounced, leading to a ratio between peak molar flow and molar flow at rest of ~11. Our setup holds great potential in capturing continuous dynamics of non-polar, low-soluble VOCs over a wide measurement range with simultaneous appraisal of decisive physiological factors affecting exhalation kinetics.Comment: 35 page

Expiratory flow rate, breath hold and anatomic dead space influence electronic nose ability to detect lung cancer

BACKGROUND: Electronic noses are composites of nanosensor arrays. Numerous studies showed their potential to detect lung cancer from breath samples by analysing exhaled volatile compound pattern ("breathprint"). Expiratory flow rate, breath hold and inclusion of anatomic dead space may influence the exhaled levels of some volatile compounds; however it has not been fully addressed how these factors affect electronic nose data. Therefore, the aim of the study was to investigate these effects. METHODS: 37 healthy subjects (44 +/- 14 years) and 27 patients with lung cancer (60 +/- 10 years) participated in the study. After deep inhalation through a volatile organic compound filter, subjects exhaled at two different flow rates (50 ml/sec and 75 ml/sec) into Teflon-coated bags. The effect of breath hold was analysed after 10 seconds of deep inhalation. We also studied the effect of anatomic dead space by excluding this fraction and comparing alveolar air to mixed (alveolar + anatomic dead space) air samples. Exhaled air samples were processed with Cyranose 320 electronic nose. RESULTS: Expiratory flow rate, breath hold and the inclusion of anatomic dead space significantly altered "breathprints" in healthy individuals (p 0.05). These factors also influenced the discrimination ability of the electronic nose to detect lung cancer significantly. CONCLUSIONS: We have shown that expiratory flow, breath hold and dead space influence exhaled volatile compound pattern assessed with electronic nose. These findings suggest critical methodological recommendations to standardise sample collections for electronic nose measurements

Laser spectroscopy for breath analysis : towards clinical implementation

Detection and analysis of volatile compounds in exhaled breath represents an attractive tool for monitoring the metabolic status of a patient and disease diagnosis, since it is non-invasive and fast. Numerous studies have already demonstrated the benefit of breath analysis in clinical settings/applications and encouraged multidisciplinary research to reveal new insights regarding the origins, pathways, and pathophysiological roles of breath components. Many breath analysis methods are currently available to help explore these directions, ranging from mass spectrometry to laser-based spectroscopy and sensor arrays. This review presents an update of the current status of optical methods, using near and mid-infrared sources, for clinical breath gas analysis over the last decade and describes recent technological developments and their applications. The review includes: tunable diode laser absorption spectroscopy, cavity ring-down spectroscopy, integrated cavity output spectroscopy, cavity-enhanced absorption spectroscopy, photoacoustic spectroscopy, quartz-enhanced photoacoustic spectroscopy, and optical frequency comb spectroscopy. A SWOT analysis (strengths, weaknesses, opportunities, and threats) is presented that describes the laser-based techniques within the clinical framework of breath research and their appealing features for clinical use.Peer reviewe

Standardised exhaled breath collection for the measurement of exhaled volatile organic compounds by proton transfer reaction mass spectrometry

BACKGROUND: Exhaled breath volatile organic compound (VOC) analysis for airway disease monitoring is promising. However, contrary to nitric oxide the method for exhaled breath collection has not yet been standardized and the effects of expiratory flow and breath-hold have not been sufficiently studied. These manoeuvres may also reveal the origin of exhaled compounds. METHODS: 15 healthy volunteers (34 +/- 7 years) participated in the study. Subjects inhaled through their nose and exhaled immediately at two different flows (5 L/min and 10 L/min) into methylated polyethylene bags. In addition, the effect of a 20 s breath-hold following inhalation to total lung capacity was studied. The samples were analyzed for ethanol and acetone levels immediately using proton-transfer-reaction mass-spectrometer (PTR-MS, Logan Research, UK). RESULTS: Ethanol levels were negatively affected by expiratory flow rate (232.70 +/- 33.50 ppb vs. 202.30 +/- 27.28 ppb at 5 L/min and 10 L/min, respectively, p < 0.05), but remained unchanged following the breath hold (242.50 +/- 34.53 vs. 237.90 +/- 35.86 ppb, without and with breath hold, respectively, p = 0.11). On the contrary, acetone levels were increased following breath hold (1.50 +/- 0.18 ppm) compared to the baseline levels (1.38 +/- 0.15 ppm), but were not affected by expiratory flow (1.40 +/- 0.14 ppm vs. 1.49 +/- 0.14 ppm, 5 L/min vs. 10 L/min, respectively, p = 0.14). The diet had no significant effects on the gasses levels which showed good inter and intra session reproducibility. CONCLUSIONS: Exhalation parameters such as expiratory flow and breath-hold may affect VOC levels significantly; therefore standardisation of exhaled VOC measurements is mandatory. Our preliminary results suggest a different origin in the respiratory tract for these two gasses

Profiles of Volatile Biomarkers Detect Tuberculosis from Skin

Tuberculosis (TB) is an infectious disease that threatens >10 million people annually. Despite advances in TB diagnostics, patients continue to receive an insufficient diagnosis as TB symptoms are not specific. Many existing biodiagnostic tests are slow, have low clinical performance, and can be unsuitable for resource-limited settings. According to the World Health Organization (WHO), a rapid, sputum-free, and cost-effective triage test for real-time detection of TB is urgently needed. This article reports on a new diagnostic pathway enabling a noninvasive, fast, and highly accurate way of detecting TB. The approach relies on TB-specific volatile organic compounds (VOCs) that are detected and quantified from the skin headspace. A specifically designed nanomaterial-based sensors array translates these findings into a point-of-care diagnosis by discriminating between active pulmonary TB patients and controls with sensitivity above 90%. This fulfills the WHO's triage test requirements and poses the potential to become a TB triage test