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Combining Thermal Desorption with Selected Ion Flow Tube Mass Spectrometry for Analyses of Breath Volatile Organic Compounds
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Analytical Chemistry

Cite this: Anal. Chem. 2024, 96, 4, 1397–1401
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https://doi.org/10.1021/acs.analchem.3c04286
Published January 20, 2024

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Abstract

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An instrument integrating thermal desorption (TD) to selected ion flow tube mass spectrometry (SIFT-MS) is presented, and its application to analyze volatile organic compounds (VOCs) in human breath is demonstrated for the first time. The rationale behind this development is the need to analyze breath samples in large-scale multicenter clinical projects involving thousands of patients recruited in different hospitals. Following adapted guidelines for validating analytical techniques, we developed and validated a targeted analytical method for 21 compounds of diverse chemical class, chosen for their clinical and biological relevance. Validation has been carried out by two independent laboratories, using calibration standards and real breath samples from healthy volunteers. The merging of SIFT-MS and TD integrates the rapid analytical capabilities of SIFT-MS with the capacity to collect breath samples across multiple hospitals. Thanks to these features, the novel instrument has the potential to be easily employed in clinical practice.

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Subjects

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Volatile organic compound (VOC) analysis within exhaled breath represents an attractive noninvasive strategy for diagnosis and therapeutic monitoring. VOCs emitted by the body reflect biochemical processes underlying physio-pathological states. (1) VOCs produced by both normal and irregular metabolism within human cells and gut bacteria may travel within systemic circulation before being released by the lungs. (2,3) Alterations of breath profiles have been reported in different diseases, (4) including different types of cancers (5,6) and respiratory diseases. (7) Breath tests are noninvasive and therefore well-accepted by patients, representing an adequate and affordable method to assess subjects with nonspecific symptoms. In a recent study, 1002 adult patients were recruited in primary care to test the acceptability and feasibility of the breath test; 98% of the recruited subjects found the test to be acceptable and easy to perform. (8) In addition, the wide applicability of breath analysis has been further proved by the high acceptability in infants and children. (9)
Despite all the advantages, breath is a complex biological matrix. Many VOCs have structural similarities and are present at low concentrations; therefore, the techniques for their analyses need to be sensitive and specific. Mass spectrometry provides high sensitivity and the possibility to identify compounds with a degree of confidence. The instruments used to analyze VOCs in breath are typically either chromatographic, with gas chromatography mass spectrometry (GC-MS) being the current gold standard, or direct sampling. Direct sampling instruments, among which one widely used for breath analysis is selected ion flow tube mass spectrometry (SIFT-MS), offer the advantage of real-time results and direct quantification. (10) Patients can directly breathe into the inlet of the instrument, without the requirement for breath collection and storage. (10) Real-time results are displayed during the analysis, which usually lasts around 1 min. However, SIFT-MS instruments in their current form are not well-suited to large-scale multicenter clinical studies, where thousands of patients are recruited, often simultaneously in different hospitals. Given the nature of analysis, the instrument would need to be located where the recruitment takes place and multicenter studies are not possible to perform. When analyzed with GC-MS, breath is collected in thermal desorption (TD) tubes containing a sorbent that has the capacity to capture VOCs. TD tubes are stored, transported, and later analyzed by a TD unit coupled to a GC-MS instrument, usually with automated methods. TD tubes are an ideal tool for clinical studies, since they are robust and easy to transport and store. In addition, breath collected onto TD tubes can remain stable for a long time. (11,12) However, the coupling with GC-MS results in slow analysis time due to the time required for efficient chromatographic separation.
The coupling of SIFT-MS with TD for VOC measurement in breath is an attractive analytical approach. The run time per sample can be drastically reduced compared to a chromatographic instrument. Development of tailored methods for specific projects can allow many samples to be run in a short time. Validated TD-SIFT-MS methods could be used in the future for high-throughput screening, in a complementary approach with GC-MS that offers the possibility of a deep untargeted analysis. (13) To date, relatively few studies have been published that describe the coupling of TD units and SIFT-MS. (14−16) However, previous work did not achieve the development of a reliable, high-throughput, and effective method that can be used in the clinical environment.
In this study we describe a novel coupling of SIFT-MS with TD. For the first time, TD and SIFT-MS interfaces have been integrated to create a novel hybrid instrument for the measurement of VOCs in human breath, with the potential to be employed in large-scale clinical projects. We developed and validated a targeted analytical method for 21 compounds, chosen for their clinical and biological relevance, following adapted European Medical Agency (EMA) guidelines for the validation of analytical techniques. (17) Validation has been carried out by two independent teams, the Hanna Group at the Department of Surgery and Cancer, Imperial College London in the United Kingdom and the Syft Technologies laboratory in New Zealand.

Experimental Section

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The experiments were carried out using a SIFT-MS instrument integrated with a thermal desorption unit and autosampler. One type of TD tube was used to optimize the method using chemical standards and real breath samples as detailed below.

SIFT-MS Instrument

The method was developed and validated using a SIFT-MS instrument (Voice200ultra model; Syft Technologies, Christchurch, New Zealand) with helium carrier gas, (1) connected to a TD 3.5+ thermal desorption unit and CIS4 UPC plus cooled injector system/transfer line (Gerstel GmbH, Mülheim an der Ruhr, Germany) with nitrogen carrier gas, and coupled with a MultiPurpose Sampler Robotic Pro autosampler (Gerstel GmbH, Mülheim an der Ruhr, Germany). SIFT-MS analysis is based on soft chemical ionization by selected reagent ions (H3O+, NO+, O2+) interacting with sample molecules. Reagent ions are produced in a microwave discharge, selected by a quadrupole mass filter, and injected into a flow of helium through the flow tube. A continuous flow of sample is admixed, and the analyte molecules react with reagent ions producing characteristic product ions. The knowledge of reaction rate constants allows the calculation of compound concentrations. (18,19) Performance of the Voice200ultra instrument is routinely optimized using the built-in validation system. (1)

TD Tubes

Biomonitoring TD tubes with a double-bed sorbent phase composed of Tenax TA/Carbograph 5TD (p/n C2-CXXX-5149; Markes International, Llantrisant, UK) were used, providing wide coverage in terms of compound type captured. The tubes were cleaned using a TC20 conditioning station (Markes International, Llantrisant, UK) following manufacturer’s recommendations (2 h, 310 °C, 100 mL/min nitrogen flow).

Chemical Standards

Twenty-one compounds were included in the method: acetic acid, acetone, benzaldehyde, butanal, butanoic acid, cyclohexane, decanal, dodecane, hexanal, hexanoic acid, isoprene, nonanal, nonanol, octanal, pentanoic acid, phenol, propanal, propanoic acid, toluene, tridecane, and undecanal. Their molecular formulas and relevant SIFT-MS reagent and product ions are listed in Table S1. The biological relevance of these compounds has been reviewed previously. (20) All analytical standards were purchased from Sigma (Sigma-Aldrich, USA), except for nonanal (Tokyo Chemical Industry, UK). Four stock solutions, one for each chemical class, were made up in methanol and freshly prepared every month. All analyte concentrations in the stock solutions were 0.025 M, except for acetic acid, isoprene, and acetone, reflecting their higher physiological breath concentrations. Working mix (250, 500, 2000, and 100 ppbv for acetic acid, isoprene, acetone and all the other VOCs respectively, considering 500 mL of breath) were made from stock solutions via serial dilution and freshly prepared every week, as well as calibration curve (CC) mix (concentrations reported in Table S2). A 1 μL sample of each CC solution was spiked onto tubes using a Calibration Solution Loading Rig (CSLR, Markes International, Llantrisant, UK). Nitrogen gas was applied to dry purge excess methanol. Methanol was included in the SIFT-MS method as a quality check, to monitor its quantity and potential effect on reagent ion depletion, and to validate dry purging effectiveness. Additionally, 1-propanol, ethanol, and ammonia were monitored in each sample run for quality control purposes. 1-Propanol and ethanol are small alcohols that may occur in ambient air at very high concentrations (ppmv) in hospital environments. Ammonia is also present at high concentrations in ambient air. (21) It is good practice to monitor their levels to ensure they do not cause depletion of reagent ions, which leads to inaccurate quantification of measured compounds. Standards of these compounds were not included in the mix since quantification was not performed.

Breath Samples

500 mL of breath was collected from healthy volunteers (REC approval: 17/WA/0161). Breath was collected through a single expiration in a Nalophan bag, connected to a breath collection system. Breath was then transferred onto two TD tubes simultaneously using a flow rate of 200 mL/min for 2.5 min, to pass a defined volume of 500 mL via each tube.

Data Analysis and Method Validation

Data acquisition was performed using the Maestro software version 1.5.4.23 (Gerstel GmbH, Mülheim an der Ruhr, Germany) and LabSyft software Pro version 1.8.1 (Syft Technologies, Christchurch, New Zealand). Data processing, further analysis, and graphical representation was performed using LabSyft and GraphPad Prism software version 9 (GraphPad software Inc., San Diego, USA). Linear regression was used to construct CCs. Limit of detection (LOD) and limit of quantification (LOQ) were calculated as the 3σ and 10σ uncertainty of the zero calibration (using the following formula LOD = (3·STEYX)/SLOPE; LOQ = (10·STEYX)/SLOPE). (22) The matrix effect was evaluated by direct slope comparison of identical CC built using chemical standards, with and without adding breath or water. The calibration range was calculated evaluating the residuals of each CC point (accepted between 80% and 120%). Method accuracy was achieved by analyzing five replicates of five calibration levels (Cal 2.5, 5, 10, 50, and 100) on three consecutive days. Accuracy was calculated as percentage of recovery and accepted when higher than 85% and lower than 115%, for all the levels except the LOQ, where it was accepted when between 80% and 120%. Precision was estimated through calculation of intra-assay and inter-assay coefficient of variation (CV%). The numerical value obtained was considered acceptable when lower than 15%. Carryover was evaluated analyzing five empty clean TD tubes after a run of the higher CC point.

Results and Discussion

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A Novel Instrument Interface

Breath TD tube analysis was achieved using a novel system, developed collaboratively by GERSTEL and Syft Technologies. This new system enables real-time analysis of desorbed volatiles from TD tubes eliminating the need for timely chromatographic separation. The thermal desorption system, consisting of a TD 3.5+ thermal desorption unit (TDU, Gerstel GmbH, Mülheim an der Ruhr, Germany), was connected to the CIS4 cooled injection system, which operated as a heated transfer line but was retained in the system to facilitate pressure control using the ePneumatics Controller (EPC, Gerstel GmbH, Mülheim an der Ruhr, Germany). This assembly, together with a heater housing, sits atop the SIFT-MS instrument, and the TDU/CIS sample line connects to the inlet capillary, which provides a constant flow rate (25 standard cubic centimeters per minute (sccm)) into the instrument for analysis. (16) For a complete design of interface, see Figure 1. A standard CIS liner packed with silanized glass wool (Crawford Scientific, Scotland, UK; OD 3 mm (ID 2 mm), length 78 mm) was used in the CIS, to protect the inlet capillary from blockage due to potential contaminating particles (e.g., dust from sorbent tubes). The ePneumatics controller stabilizes and monitors both the desorption gas flow going through the TD tube and the pressure at the downstream end of the TD tube, at the point where the flow splits between the SIFT-MS inlet and the split excess exhaust. The SIFT-MS inlet flow can be adjusted by changing the pressure to reach a desired split-ratio. At both sites, automation of analysis was achieved using an MPS autosampler, enabling unattended analysis with a high throughput. The perfect integration of the different parts made online TD-SIFT-MS sample analysis possible, by mimicking the original direct system typical of the SIFT-MS technique. Further, due to the humidity robustness of SIFT-MS instruments with helium carrier gas, it was not necessary to prepurge breath samples prior to analysis, as is typical for TD-GC analyses. This minimizes the loss of analyte during purging, enhancing the comparability between TD- and direct SIFT-MS.

Figure 1

Figure 1. Novel interface designed for the coupling of TD and SIFT.

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Method Development

Twenty-one compounds of diverse chemical class (acetic acid, acetone, benzaldehyde, butanal, butanoic acid, cyclohexane, decanal, dodecane, hexanal, hexanoic acid, isoprene, nonanal, nonanol, octanal, pentanoic acid, phenol, propanal, propanoic acid, toluene, tridecane, and undecanal), chosen for their biological relevance and their role assessed in previous clinical studies, (5,23) were targeted in the TD-SIFT-MS analyses. All the compounds included in the analytical method with formula, reagent ion, reaction rate, branching ratio and product ion are summarized in Table S1. Product ion conflicts were resolved using different reagent ions. Different nitrogen flows and purging times were tested to eliminate the excess of methanol. The best values in terms of lower methanol content and analyte loss were obtained using a flow of nitrogen of 135 mL/min through the TD tube for 3 min after standard spiking. This process is necessary for TD tubes spiked with standards dissolved in methanol, but it was not applied for breath samples, since there is no need to dry purge. SIFT-MS is immune to the effects of the water vapor present in breath, and humidity measurement can be used as an additional quality control for adequate breath sampling. (1) The TD-SIFT-MS analytical method was developed to optimize time resolution of the desorption profile measurement, while enabling the maximum number of analytes to be targeted. Figure 2 shows an example desorption profile of the working mix, containing all compounds included in the method. TD parameters were also optimized. Three desorption temperatures were tested using constant initial temperature, temperature ramp, and a minimum split ratio. The optimal desorption temperature was assessed to be 260 °C. Three values were tested also for the temperature ramp rate, with 160 °C/min giving the best results in terms of analyte desorption profile. Split ratio was optimized to find the best value assuring good sensitivity and avoiding instrument overload. After testing different split ratios, 0.2:1 was chosen. This value represents the minimum value allowed by the Maestro software, assuring minimal compound loss. TD optimized parameters used for the method are summarized in Table 1.

Figure 2

Figure 2. Raw desorption profile of the 21 compounds included in the analytical method, the five compounds monitored for quality purpose and humidity.

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Table 1. Final Desorption Parameters Optimized
Desorption Temperature (°C)260
Temperature Ramp (°C per min)160
Hold Time (min)3
Split Ratio0.2:1
Transfer Line Temperature (°C)200
Standby Temperature (°C)50

Method Validation

Validation of the analytical method was performed following the guidelines on bioanalytical method validation provided by the EMA, (17) adapted to breath analysis. The validation process was carried out in parallel at the Department of Surgery and Cancer of Imperial College London, London, UK (ICL) and at the Syft Technologies Laboratory, Christchurch, New Zealand (Syft). To overcome the absence of a surrogate matrix, with all breath biological characteristics but without compounds of interest, we used authentic breath from healthy volunteers and water matrices during the validation. Linearity and matrix effect were tested for all the compounds spiking CC pure standards on TD tubes only (triplicates), in combination with water (1 μL, Milli-Q, in duplicates) or breath from healthy volunteers (500 mL, in duplicates). Endogenous content of targeted analytes was subtracted from all the breath CC points. Slopes, intercepts, linear regression coefficient (R2), calibration range, LOD, and LOQ found by each laboratory carrying out the validation are listed for each compound and matrix in Table S3. Acetic acid, acetone, and isoprene had a higher calibration range compared to all other compounds, due to their higher physiological concentrations in breath, and this is reflected in the LOD and LOQ calculated values. For acetone and isoprene, it was not possible to determine a precise calibration range, LOD, and LOQ in breath matrix since the content of these two compounds in the breath obtained from volunteers and used to build the CC was too high and “masked” the spiked standard. The CCs were consistent in terms of slopes for all the compounds across the three biological matrices for both ICL and Syft data sets (figure S1). Accuracy was calculated between 85% and 115% of the theoretical value for all compounds, at all five calibration levels in both laboratories, with few exceptions. Similar results were obtained for the precision, intraday, and interday measurements. All CV% results were lower than the established threshold of 15%, except for a few cases (higher calculated value outside acceptance limit: 22%, intraday precision for propanal lower level at Syft). The measured levels with standard deviation, accuracy, CV% intraday, and CV% interday are presented in Table S4. These data showcase the good repeatability of the method on different days and concentration ranges. Carryover was also tested by analyzing five empty conditioned TD tubes after a run at the higher CC point. For both analyses carried out at ICL and at Syft, carryover was absent for all compounds (data not shown).
The use of liquid standards dissolved in methanol to build a CC for quantification of gaseous compounds is widely accepted, but it may be not perfectly accurate. The behavior of some of the compounds, for example in the interaction with the sorbent phase of the TD tubes, could present some differences, and the chemical standards used for the calibration may not be fully representative of the molecules measured in the breath. The use of gaseous standards, on the other hand, presents practical limitations that would have reduced the applicability of the method in both clinical practice and high-throughput analysis scenarios, negating one of the main advantages of the TD-SIFT-MS application. In general, the use of Biomonitoring TD tubes was not a perfect fit for all analytes. Fatty acids, especially acetic acid, are likely more suitably trapped on an alternative sorbent. The use of these tubes represents a compromise to extend the coverage of different compounds included in the method, ranging from C2 to C13.

Conclusions

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The combination of SIFT-MS and TD brings together the analysis speed and user-friendly features of SIFT-MS with the possibility to collect breath in a multicenter fashion given by TD tubes. This novel instrument has the potential to be easily employed in clinical settings for targeted analysis, using quick and completely automated analytical methods.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.analchem.3c04286.

  • Calibration curves in different matrices (Figure S1); list of compounds included in the analytical method (Table S1); concentrations of each calibration curve point (Table S2); linearity, LOD, and LOQ obtained at Imperial College London and Syft Technologies (Table S3); accuracy and precision obtained at Imperial College London and Syft Technologies (Table S4) (PDF)

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Author Information

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  • Corresponding Author
  • Authors
    • Ilaria Belluomo - Department of Surgery and Cancer, Imperial College London, London W12 0HS, United Kingdom;  Orcidhttps://orcid.org/0000-0002-8637-0285
    • Sophia E. Whitlock - Syft Technologies Limited, 68 St. Asaph Street, Christchurch 8011, New Zealand
    • Antonis Myridakis - Department of Surgery and Cancer, Imperial College London, London W12 0HS, United Kingdom;  Present Address: Centre for Pollution Research & Policy, Environmental Sciences, Brunel University London, UB8 3PH, United Kingdom;  Orcidhttps://orcid.org/0000-0003-1690-6651
    • Aaron G. Parker - Department of Surgery and Cancer, Imperial College London, London W12 0HS, United Kingdom
    • Valerio Converso - Department of Surgery and Cancer, Imperial College London, London W12 0HS, United Kingdom;  Orcidhttps://orcid.org/0000-0002-3461-8891
    • Mark J. Perkins - Element Lab Solutions, Wellbrook Court, Girton Road, Cambridge CB3 0NA, United Kingdom
    • Vaughan S. Langford - Syft Technologies Limited, 68 St. Asaph Street, Christchurch 8011, New Zealand;  Orcidhttps://orcid.org/0000-0001-8059-5750
    • Patrik Španěl - Department of Surgery and Cancer, Imperial College London, London W12 0HS, United Kingdom;  J. Heyrovský Institute of Physical Chemistry of the Czech Academy of Sciences, 182 23 Prague, Czechia;  Orcidhttps://orcid.org/0000-0002-9868-8282
  • Author Contributions

    The manuscript was written through the contributions of all authors.

  • Notes
    The authors declare the following competing financial interest(s): G.B.H. is the founder of a company for early detection of cancer.

Acknowledgments

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This project was supported by Royal Society of Chemistry through the Research Fund. This research was also supported by Wellcome Trust, Surgery and Cancer Department, Imperial College London and NIHR London In Vitro Diagnostics Co-operative. The authors would like to thank Kurt Thaxton, Dirk Bremer, and Eike Kleine-Benne from Gerstel. S.E.W. and V.S.L. also acknowledge Drs. Daniel Milligan, Diandree Padayachee, and Juby Mathew of Syft Technologies for helpful discussions.

References

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This article references 23 other publications.

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    Importance: Early esophagogastric cancer (OGC) stage presents with nonspecific symptoms. Objective: The aim of this study was to determine the accuracy of a breath test for the diagnosis of OGC in a multicenter validation study. Design, Setting, and Participants: Patient recruitment for this diagnostic validation study was conducted at 3 London hospital sites, with breath samples returned to a central laboratory for selected ion flow tube mass spectrometry (SIFT-MS) analysis. Based on a 1:1 cancer:control ratio, and maintaining a sensitivity and specificity of 80%, the sample size required was 325 patients. All patients with cancer were on a curative treatment pathway, and patients were recruited consecutively. Among the 335 patients included; 172 were in the control group and 163 had OGC. Interventions: Breath samples were collected using secure 500-mL steel breath bags and analyzed by SIFT-MS. Quality assurance measures included sampling room air, training all researchers in breath sampling, regular instrument calibration, and unambiguous volatile organic compounds (VOCs) identification by gas chromatography mass spectrometry. Main Outcomes and Measures: The risk of cancer was identified based on a previously generated 5-VOCs model and compared with histopathology-proven diagnosis. Results: Patients in the OGC group were older (median [IQR] age 68 [60-75] vs 55 [41-69] years) and had a greater proportion of men (134 [82.2%]) vs women (81 [47.4%]) compared with the control group. Of the 163 patients with OGC, 123 (69%) had tumor stage T3/4, and 106 (65%) had nodal metastasis on clinical staging. The predictive probabilities generated by this 5-VOCs diagnostic model were used to generate a receiver operator characteristic curve, with good diagnostic accuracy, area under the curve of 0.85. This translated to a sensitivity of 80% and specificity of 81% for the diagnosis of OGC. Conclusions and Relevance: This study shows the potential of breath analysis in noninvasive diagnosis of OGC in the clinical setting. The next step is to establish the diagnostic accuracy of the test among the intended population in primary care where the test will be applied.
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    Diagnostic Performance of a Noninvasive Breath Test for Colorectal Cancer: COBRA1 Study
    Woodfield, Georgia; Belluomo, Ilaria; Laponogov, Ivan; Veselkov, Kirill; Cross, Amanda J.; Hanna, George B.
    Gastroenterology (2022), 163 (5), 1447-1449.e8CODEN: GASTAB; ISSN:0016-5085. (Elsevier Inc.)
    An intermediate triage test to identify patients at risk of Colorectal Cancer could streamline referral pathways. The target sample size was 1463 patients (117 CRC, 1346 control subjects) using the power diagnostic test function from the MKmisc R package, considering type I error (alpha) of 0.05, power (1-beta) of 0.8, prevalence value of 0.08, and assumed difference of 0.1. The study recruited patients aged 18-90 years attending 7 London hospitals for a bowel cancer screening program colonoscopy because of a pos. fecal occult blood test (n 664), colonoscopy for other indications (n 645), or surgical colorectal adenocarcinoma resection (n 123) (June 2017 to Feb. 2020). Included in the anal. were 1432 patients (828 men), with a median age of 66.5 years (range, 18-90). No adverse events were reported. Of 1432 patients, 357 had a normal colonoscopy; 188 had benign pathol. (hemorrhoids or diverticular disease); 106 had inflammatory bowel disease; 348, 67, and 204 patients had low-, intermediate- and highrisk polyps, resp.; and 162 had colorectal adenocarcinoma.
  7. 7
    Kamal, F.; Kumar, S.; Edwards, M. R.; Veselkov, K.; Belluomo, I.; Kebadze, T.; Romano, A.; Trujillo-Torralbo, M. B.; Shahridan Faiez, T.; Walton, R. Virus-induced Volatile Organic Compounds Are Detectable in Exhaled Breath during Pulmonary Infection. Am. J. Respir Crit Care Med. 2021, 204 (9), 1075– 1085,  DOI: 10.1164/rccm.202103-0660OC
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    Virus-induced volatile organic compounds are detectable in exhaled breath during pulmonary infection
    Kamal, Faisal; Kumar, Sacheen; Edwards, Michael R.; Veselkov, Kirill; Belluomo, Ilaria; Kebadze, Tatiana; Romano, Andrea; Trujillo-Torralbo, Maria-Belen; Faiez, Tasnim Shahridan; Walton, Ross; Ritchie, Andrew I.; Wiseman, Dexter J.; Laponogov, Ivan; Donaldson, Gavin; Wedzicha, Jadwiga A.; Johnston, Sebastian L.; Singanayagam, Aran; Hanna, George B.
    American Journal of Respiratory and Critical Care Medicine (2021), 204 (9), 1075-1085CODEN: AJCMED; ISSN:1073-449X. (American Thoracic Society)
    Chronic obstructive pulmonary disease (COPD) is a condition punctuated by acute exacerbations commonly triggered by viral and/or bacterial infection. Early identification of exacerbation triggers is important to guide appropriate therapy, but currently available tests are slow and imprecise. Volatile org. compds. (VOCs) can be detected in exhaled breath and have the potential to be rapid tissue-specific biomarkers of infection etiol. Objectives: To det. whether volatile org. compd. measurement could distinguish viral from bacterial infection in COPD. We used serial sampling within in vitro and in vivo studies to elucidate the dynamic changes that occur in VOC prodn. during acute respiratory viral infection. Highly sensitive gas chromatog.-mass spectrometry techniques were used to measure VOC prodn. from infected airway epithelial-cell cultures and in exhaled breath samples from healthy subjects exptl. challenged with rhinovirus (RV)-A16 and from subjects with COPD with naturally occurring exacerbations. Measurements and Main Results: We identified a novel VOC signature comprising decane and other long-chain alkane compds. that is induced during RV infection of cultured airway epithelial cells and is also increased in the exhaled breath from healthy subjects exptl. challenged with RV and from patients with COPD during naturally occurring viral exacerbations. These compds. correlated with the magnitude of antiviral immune responses, viral burden, and exacerbation severity but were not induced by bacterial infection, suggesting that they represent a specific virus-inducible signature. Our study highlights the potential for measurement of exhaled breath VOCs as rapid, noninvasive biomarkers of viral infection. Further studies are needed to det. whether measurement of these signatures could be used to guide more targeted therapy with antibiotic/antiviral agents for COPD exacerbations.
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    Woodfield, G.; Belluomo, I.; Boshier, P. R.; Waller, A.; Fayyad, M.; von Wagner, C.; Cross, A. J.; Hanna, G. B. Feasibility and acceptability of breath research in primary care: a prospective, cross-sectional, observational study. BMJ. Open 2021, 11 (4), e044691  DOI: 10.1136/bmjopen-2020-044691
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    Weber, R.; Haas, N.; Baghdasaryan, A.; Bruderer, T.; Inci, D.; Micic, S.; Perkins, N.; Spinas, R.; Zenobi, R.; Moeller, A. Volatile organic compound breath signatures of children with cystic fibrosis by real-time SESI-HRMS. ERJ. Open Res. 2020, 6 (1), 00171-2019,  DOI: 10.1183/23120541.00171-2019
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    Bruderer, T.; Gaisl, T.; Gaugg, M. T.; Nowak, N.; Streckenbach, B.; Muller, S.; Moeller, A.; Kohler, M.; Zenobi, R. On-Line Analysis of Exhaled Breath Focus Review. Chem. Rev. 2019, 119 (19), 10803– 10828,  DOI: 10.1021/acs.chemrev.9b00005
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    On-Line Analysis of Exhaled Breath
    Bruderer, Tobias; Gaisl, Thomas; Gaugg, Martin T.; Nowak, Nora; Streckenbach, Bettina; Muller, Simona; Moeller, Alexander; Kohler, Malcolm; Zenobi, Renato
    Chemical Reviews (Washington, DC, United States) (2019), 119 (19), 10803-10828CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. Online anal. of exhaled breath offers insight into a person's metab. without the need for sample prepn. or sample collection. Due to its noninvasive nature and the possibility to sample continuously, the anal. of breath has great clin. potential. The unique features of this technol. make it an attractive candidate for applications in medicine, beyond the task of diagnosis. The authors review the current methodologies for online breath anal., discuss current and future applications, and critically evaluate challenges and pitfalls such as the need for standardization. Special emphasis is given to the use of the technol. in diagnosing respiratory diseases, potential niche applications, and the promise of breath anal. for personalized medicine. The anal. methodologies used range from very small and low-cost chem. sensors, which are ideal for continuous monitoring of disease status, to optical spectroscopy and state-of-the-art, high-resoln. mass spectrometry. The latter can be used for untargeted anal. of exhaled breath, with the capability to identify hitherto unknown mols. The interpretation of the resulting big data sets is complex and often constrained due to a limited no. of participants. Even larger data sets will be needed for assessing reproducibility and for validation of biomarker candidates. In addn., mol. structures and quantification of compds. are generally not easily available from online measurements and require complementary measurements, for example, a sepn. method coupled to mass spectrometry. Furthermore, a lack of standardization still hampers the application of the technique to screen larger cohorts of patients. This review summarizes the present status and continuous improvements of the principal online breath anal. methods and evaluates obstacles for their wider application.
  11. 11
    Harshman, S. W.; Mani, N.; Geier, B. A.; Kwak, J.; Shepard, P.; Fan, M.; Sudberry, G. L.; Mayes, R. S.; Ott, D. K.; Martin, J. A.; Grigsby, C. C. Storage stability of exhaled breath on Tenax TA. J. Breath Res. 2016, 10 (4), 046008,  DOI: 10.1088/1752-7155/10/4/046008
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    11
    Storage stability of exhaled breath on Tenax TA
    Harshman, Sean W.; Mani, Nilan; Geier, Brian A.; Kwak, Jae; Shepard, Phillip; Fan, Maomian; Sudberry, Gregory L.; Mayes, Ryan S.; Ott, Darrin K.; Martin, Jennifer A.; Grigsby, Claude C.
    Journal of Breath Research (2016), 10 (4), 046008/1-046008/12CODEN: JBROBW; ISSN:1752-7155. (IOP Publishing Ltd.)
    Exhaled breath is coming to the forefront of non-invasive biomarker discovery efforts. Concn. of exhaled breath volatile org. compds. (VOCs) on thermal desorption (TD) tubes with subsequent anal. by gas chromatog.-mass spectrometry (GC-MS) has dominated this field. As discovery experimentation increases in frequency, the need to evaluate the long-term storage stability of exhaled breath VOCs on thermal desorption adsorbent material is crit. To address this gap, exhaled breath was loaded on Tenax TA thermal desorption tubes and stored at various temp. conditions. 74 VOCs, 56 of which have been previously uncharacterized, were monitored using GC-MS over a period of 31 d. The results suggest that storage of exhaled breath at cold temps. (4 °C) provides the most consistent retention of exhaled breath VOCs temporally. Samples were detd. to be stable up to 14 d across storage conditions prior to gaining or losing 1-2 std. deviations in abundance. Through gene set enrichment anal. (GSEA), certain chem. classes were found to be pos. (acids) or neg. (sulfur-contg.) enriched temporally. By means of field sample collections, the effect of storage and shipping was found to be similar to those studies preformed in the lab. at 4 °C. Collectively this study not only provides recommendations for proper storage conditions and storage length, but also illustrates the use of GSEA to exhaled breath based GC-MS data.
  12. 12
    Kang, S.; Paul Thomas, C. L. How long may a breath sample be stored for at −80 degrees C? A study of the stability of volatile organic compounds trapped onto a mixed Tenax:Carbograph trap adsorbent bed from exhaled breath. J. Breath Res. 2016, 10 (2), 026011,  DOI: 10.1088/1752-7155/10/2/026011
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    12
    How long may a breath sample be stored for at -80 °C? A study of the stability of volatile organic compounds trapped onto a mixed Tenax:Carbograph trap adsorbent bed from exhaled breath
    Kang, S.; Paul Thomas, C. L.
    Journal of Breath Research (2016), 10 (2), 026011/1-026011/11CODEN: JBROBW; ISSN:1752-7155. (IOP Publishing Ltd.)
    Thermal desorption is used extensively in exhaled breath volatile org. compd. (VOC) anal., and it is often necessary to store the adsorbent tube samples before anal. The possible introduction of storage artifacts is an important potential confounding factor in the development of std. methodologies for breath sampling and anal. The stability of VOCs trapped from breath samples onto a dual bed Tenax TA:Carbograph adsorbent tube and stored °80°C was studied over 12.5 mo. 25 samples were collected from a single male participant over 3h and then stored at °80 °C. Randomly selected adsorbent tubes were subsequent analyzed by thermal desorption-gas chromatog.-mass spectrometry at 5 times points throughout the 12.5 mo of the study. Toluene-d8, decane-d22 and hexadecane-d34 internal stds. were used to manage the instrument variability throughout the duration of the study. A breath-matrix consisting of 161 endogenous and 423 exogenous VOC was created. Iterative orthogonal partial least squared discriminant anal. (OPLS-DA) and principal components anal. (PCA) indicated that it was not possible to detect storage artifacts at 1.5 mo storage. By 6 mo storage artifacts were discernible with significant changes obsd. for 27% of the recovered VOC. Endogenous VOC were obsd. to be more susceptible to storage. A paired two-tailed t-test on the endogenous compds. indicated that the max. storage duration under these conditions was 1.5 mo with 94% of the VOCs stable. This study indicates that a prudent approach is best adopted for the storage of adsorbent samples; storage times should be minimised, and storage time examd. as a possible discriminatory factor in multivariate anal.
  13. 13
    Stefanuto, P. H.; Zanella, D.; Vercammen, J.; Henket, M.; Schleich, F.; Louis, R.; Focant, J. F. Multimodal combination of GC x GC-HRTOFMS and SIFT-MS for asthma phenotyping using exhaled breath. Sci. Rep 2020, 10 (1), 16159,  DOI: 10.1038/s41598-020-73408-2
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    13
    Multimodal combination of GC x GC-HRTOFMS and SIFT-MS for asthma phenotyping using exhaled breath
    Stefanuto, Pierre-Hugues; Zanella, Delphine; Vercammen, Joeri; Henket, Monique; Schleich, Florence; Louis, Renaud; Focant, Jean-Francois
    Scientific Reports (2020), 10 (1), 16159CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
    Chronic inflammatory lung diseases impact more than 300 million of people worldwide. Because they are not curable, these diseases have a high impact on both the quality of life of patients and the healthcare budget. The stability of patient condition relies mostly on const. treatment adaptation and lung function monitoring. However, due to the variety of inflammation phenotypes, almost one third of the patients receive an ineffective treatment. To improve phenotyping, we evaluated the complementarity of two techniques for exhaled breath anal.: full resolving comprehensive two-dimensional gas chromatog. coupled to high-resoln. time-of-flight mass spectrometry (GC x GC-HRTOFMS) and rapid screening selected ion flow tube MS (SIFT-MS). GC x GC-HRTOFMS has a high resolving power and offers a full overview of sample compn., providing deep insights on the ongoing biol. SIFT-MS is usually used for targeted analyses, allowing rapid classification of samples in defined groups. In this study, we used SIFT-MS in a possible untargeted full-scan mode, where it provides pattern-based classification capacity. We analyzed the exhaled breath of 50 asthmatic patients. Both techniques provided good classification accuracy (around 75%), similar to the efficiency of other clin. tools routinely used for asthma phenotyping. Moreover, our study provides useful information regarding the complementarity of the two techniques.
  14. 14
    Hryniuk, A.; Ross, B. M. Detection of acetone and isoprene in human breath using a combination of thermal desorption and selected ion flow tube mass spectrometry. Int. J. Mass Spectrom. 2009, 285 (1–2), 26– 30,  DOI: 10.1016/j.ijms.2009.02.027
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    14
    Detection of acetone and isoprene in human breath using a combination of thermal desorption and selected ion flow tube mass spectrometry
    Hryniuk, Alexa; Ross, Brian M.
    International Journal of Mass Spectrometry (2009), 285 (1-2), 26-30CODEN: IMSPF8; ISSN:1387-3806. (Elsevier B.V.)
    The measurement of volatile chems. in human exhalant (breath anal.) has recently emerged as a non-invasive technique with the potential for the early diagnosis of disease. A common method of volatile chem. collection is to capture gases onto a solid phase sorbent followed, at a later time, by thermal release and anal. This technique, termed thermal desorption (TD), may be a useful means to collect and store breath volatiles in a clin. setting prior to anal. TD is, however, normally used in conjunction with gas chromatog. (TD-GC) which results in slow anal. times and the required use of chem. stds. The new technique of selected ion flow tube mass spectrometry (SIFT-MS) offers a more rapid anal. process without the need for stds. SIFT-MS is normally used to analyze gas concn. in real-time and it is unclear whether combined TD and SIFT-MS can be successfully employed for breath anal. We found that there was an approx. 1 to 1 concordance between levels of isoprene or acetone in the breath of 12 healthy volunteers measured either using real-time SIFT-MS or offline using a combination of SIFT-MS and TD (TD-SIFT-MS). The use of higher vols. of human breath did impact TD-SIFT-MS measurements of isoprene (but not acetone) with an apparent ceiling effect being obsd. Nevertheless our findings demonstrate the potential for breath anal. using a combination of TD and SIFT-MS, an approach which may find utility in a clin. setting which does not allow online anal. of breath.
  15. 15
    Sovova, K.; Spesyvyi, A.; Bursova, M.; Pasztor, P.; Kubista, J.; Shestivska, V.; Spanel, P. Time-integrated thermal desorption for quantitative SIFT-MS analyses of atmospheric monoterpenes. Anal. Bioanal. Chem. 2019, 411 (14), 2997– 3007,  DOI: 10.1007/s00216-019-01782-6
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    Time-integrated thermal desorption for quantitative SIFT-MS analyses of atmospheric monoterpenes
    Sovova, Kristyna; Spesyvyi, Anatolii; Bursova, Miroslava; Pasztor, Pavel; Kubista, Jiri; Shestivska, Violetta; Spanel, Patrik
    Analytical and Bioanalytical Chemistry (2019), 411 (14), 2997-3007CODEN: ABCNBP; ISSN:1618-2642. (Springer)
    A new time-integrated thermal desorption technique has been developed that can be used with selected ion flow tube mass spectrometry, TI-TD/SIFT-MS, for off-line quant. analyses of VOCs accumulated onto sorbents. Using a slow desorption temp. ramp, the abs. amts. of desorbed compds. can be quantified in real time by SIFT-MS and constitutional isomers can be sepd. To facilitate application of this technique to environmental atm. monitoring, method parameters were optimized for quantification of the three common atm. monoterpenes: β-pinene, R-limonene and 3-carene. Three sorbent types, Tenax TA, Tenax GR and Porapak Q, were tested under 26 different desorption conditions detd. by the "design of expt.", DOE, systematic approach. The optimal combination of type of sorbent, bed length, sampling flow rate, sample vol. and the initial desorption temp. was detd. from the exptl. results by ANOVA. Porapak Q exhibited better efficiency of sample collection and further extn. for total monoterpene concn. measurements. However, Tenax GR or TA enabled sepn. of all three monoterpenes. The results of this lab. study were tested with the sample accumulated from a branch of a Pinus nigra tree.
  16. 16
    Slingers, G.; Eede, M. V.; Lindekens, J.; Spruyt, M.; Goelen, E.; Raes, M.; Koppen, G. Real-time versus thermal desorption selected ion flow tube mass spectrometry for quantification of breath volatiles. Rapid Commun. Mass Spectrom. 2021, 35 (4), e8994,  DOI: 10.1002/rcm.8994
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    Real-time versus thermal desorption selected ion flow tube mass spectrometry for quantification of breath volatiles
    Slingers, Gitte; Vanden Eede, Martin; Lindekens, Jill; Spruyt, Maarten; Goelen, Eddy; Raes, Marc; Koppen, Gudrun
    Rapid Communications in Mass Spectrometry (2021), 35 (4), e8994CODEN: RCMSEF; ISSN:0951-4198. (John Wiley & Sons Ltd.)
    Rationale : Selected ion flow tube mass spectrometry (SIFT-MS) is versatile, rapidly provides result output and dets. a wide range of volatiles, making it suitable for biomedical applications. When direct sampling into the SIFT-MS instrument is impractical, combining thermal desorption (TD) and SIFT-MS might offer a soln. as it allows sample storage on sorbent tubes for later anal. This work compares off-line TD SIFT-MS and real-time SIFT-MS for the quantification of selected breath volatiles. Methods : Ten healthy non-smoking individuals provided 60 breath samples per method. For off-line anal., breath was collected onto sorbent tubes via a breath sampler provided with filtered inspiratory air. After TD, samples were re-collected in Tedlar bags which were then connected to the SIFT-MS instrument. For real-time anal., breath was sampled directly into the instrument. In both cases the anal. method included a total of 155 product ions, and 14 selected volatiles were quantified. The agreement between the methods was assessed using Pearson correlation coeffs. and Bland-Altman plots. Results : Overall, correlations between real-time and off-line anal. were moderate to very strong (r = 0.43-0.92) depending on the volatile of interest, except for 2,3-butanedione and styrene. The difference between real-time and off-line measured breath concns. (av. bias) ranged between -14.57 and 20.48 ppbv. For acetone and isoprene, it was 251.53 and 31.9 ppbv, resp. Conclusions : Real-time SIFT-MS and off-line TD SIFT-MS for quantification of selected breath volatiles did not show optimal agreement. Analyzing a multitude of analytes in breath via direct exhalation into a SIFT-MS instrument for real-time anal. is challenging. On the other hand, off-line anal. using a breath collection device also has its issues such as possible sample losses due to selective absorption depending on the sorbent used or during desorption and transfer to the instrument. Despite these drawbacks, both methods were moderately well correlated.
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    Smith, D.; Spanel, P.; Demarais, N.; Langford, V. S.; McEwan, M. J. Recent developments and applications of selected ion flow tube mass spectrometry (SIFT-MS). Mass Spectrom Rev. 2023, e21835  DOI: 10.1002/mas.21835
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    Spanel, P.; Dryahina, K.; Smith, D. A general method for the calculation of absolute trace gas concentrations in air and breath from selected ion flow tube mass spectrometry data. Int. J. Mass Spectrom. 2006, 249, 230– 239,  DOI: 10.1016/j.ijms.2005.12.024
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    19
    A general method for the calculation of absolute trace gas concentrations in air and breath from selected ion flow tube mass spectrometry data
    Spanel, Patrik; Dryahina, Kseniya; Smith, David
    International Journal of Mass Spectrometry (2006), 249/250 (), 230-239CODEN: IMSPF8; ISSN:1387-3806. (Elsevier B.V.)
    A complete description is presented of a numerical method that allows the calcn., in real time, of abs. concns. of trace gases, including volatile org. compds. and water vapor, from selected ion flow tube mass spectrometry, SIFT-MS, data. No assumptions are made concerning the SIFT-MS instrument size or its configuration and thus the calcn. can be applied to the currently available, relatively large instruments and the anticipated new generation of smaller SIFT-MS instruments. This numerical method clearly distinguishes those parameters that are obviously specific to a particular instrument, including flow tube geometry, degree of mass discrimination in the anal. mass spectrometer and flow tube reaction time, from general fundamental processes, in particular the differential diffusive loss of ions along the flow tube that is dependent on the properties of those ions involved in the detn. of the concns. of particular trace gases. The essential reaction and transport kinetics are outlined, which describe the formation and loss of the product ions formed in the chem. ionization of the trace gases by the precursor ions. A generalized calcn. of the required ionic diffusion coeffs. is introduced with options either for their accurate detn. from the mol. geometry of ions or for less accurate but simpler ests. obtained using just the ionic mass. Based on the above ideas, a straightforward calcn. sequence is shown to det. trace gas concns. by SIFT-MS, and its utility demonstrated by an example of the anal. of acetone in exhaled breath.
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    Drabinska, N.; Flynn, C.; Ratcliffe, N.; Belluomo, I.; Myridakis, A.; Gould, O.; Fois, M.; Smart, A.; Devine, T.; Costello, B. L. A literature survey of all volatiles from healthy human breath and bodily fluids: the human volatilome. J. Breath Res. 2021, 15 (3), 034001,  DOI: 10.1088/1752-7163/abf1d0
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    Behera, S. N.; Sharma, M.; Aneja, V. P.; Balasubramanian, R. Ammonia in the atmosphere: a review on emission sources, atmospheric chemistry and deposition on terrestrial bodies. Environ. Sci. Pollut Res. Int. 2013, 20 (11), 8092– 8131,  DOI: 10.1007/s11356-013-2051-9
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    Ammonia in the atmosphere: a review on emission sources, atmospheric chemistry and deposition on terrestrial bodies
    Behera Sailesh N; Sharma Mukesh; Aneja Viney P; Balasubramanian Rajasekhar
    Environmental science and pollution research international (2013), 20 (11), 8092-131 ISSN:.
    Gaseous ammonia (NH3) is the most abundant alkaline gas in the atmosphere. In addition, it is a major component of total reactive nitrogen. The largest source of NH3 emissions is agriculture, including animal husbandry and NH3-based fertilizer applications. Other sources of NH3 include industrial processes, vehicular emissions and volatilization from soils and oceans. Recent studies have indicated that NH3 emissions have been increasing over the last few decades on a global scale. This is a concern because NH3 plays a significant role in the formation of atmospheric particulate matter, visibility degradation and atmospheric deposition of nitrogen to sensitive ecosystems. Thus, the increase in NH3 emissions negatively influences environmental and public health as well as climate change. For these reasons, it is important to have a clear understanding of the sources, deposition and atmospheric behaviour of NH3. Over the last two decades, a number of research papers have addressed pertinent issues related to NH3 emissions into the atmosphere at global, regional and local scales. This review article integrates the knowledge available on atmospheric NH3 from the literature in a systematic manner, describes the environmental implications of unabated NH3 emissions and provides a scientific basis for developing effective control strategies for NH3.
  22. 22
    Spanel, P.; Spesyvyi, A.; Smith, D. Electrostatic Switching and Selection of H(3)O(+), NO(+), and O(2)(+*) Reagent Ions for Selected Ion Flow-Drift Tube Mass Spectrometric Analyses of Air and Breath. Anal. Chem. 2019, 91 (8), 5380– 5388,  DOI: 10.1021/acs.analchem.9b00530
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    22
    Electrostatic Switching and Selection of H3O+, NO+, and O2+• Reagent Ions for Selected Ion Flow-Drift Tube Mass Spectrometric Analyses of Air and Breath
    Spanel, Patrik; Spesyvyi, Anatolii; Smith, David
    Analytical Chemistry (Washington, DC, United States) (2019), 91 (8), 5380-5388CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    Soft chem. ionization mass spectrometry techniques, particularly the well-established proton transfer reaction mass spectrometry, PTR-MS, and selected ion flow tube mass spectrometry, SIFT-MS, are widely used for real-time quantification of volatile org. compds. in ambient air and exhaled breath with applications ranging from environmental science to medicine. The most common reagent ions H3O+, NO+, or O2+• can be selected either by quadrupole mass filtering from a discharge ion source, which is relatively inefficient, or by switching the gas/vapor in the ion source, which is relatively slow. The chosen reagent ions are introduced into a flow tube or flow-drift tube reactor where they react with analyte mols. in sample gas. This article describes a new electrostatic reagent ion switching, ERIS, technique by which H3O+, NO+, and O2+• reagent ions, produced simultaneously in three sep. gas discharges, can be purified in post-discharge source drift tubes, switched rapidly, and selected for transport into a flow-drift tube reactor. The construction of the device and the ion-mol. chem. exploited to purify the individual reagent ions are described. The speed and sensitivity of ERIS coupled to a selected ion flow-drift tube mass spectrometry, SIFDT-MS, is demonstrated by the simultaneous quantification of methanol with H3O+, acetone with NO+, and di-Me sulfide with O2+• reagent ions in single breath exhalations. The present ERIS approach is preferable to the previously used quadrupole filtering, as it increases anal. sensitivity of the SIFDT-MS instrument while reducing its size and the required no. of vacuum pumps.
  23. 23
    Kumar, S.; Huang, J.; Abbassi-Ghadi, N.; Mackenzie, H. A.; Veselkov, K. A.; Hoare, J. M.; Lovat, L. B.; Spanel, P.; Smith, D.; Hanna, G. B. Mass Spectrometric Analysis of Exhaled Breath for the Identification of Volatile Organic Compound Biomarkers in Esophageal and Gastric Adenocarcinoma. Ann. Surg 2015, 262 (6), 981– 990,  DOI: 10.1097/SLA.0000000000001101
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    23
    Mass Spectrometric Analysis of Exhaled Breath for the Identification of Volatile Organic Compound Biomarkers in Esophageal and Gastric Adenocarcinoma
    Kumar Sacheen; Huang Juzheng; Abbassi-Ghadi Nima; Mackenzie Hugh A; Veselkov Kirill A; Hoare Jonathan M; Lovat Laurence B; Spanel Patrik; Smith David; Hanna George B
    Annals of surgery (2015), 262 (6), 981-90 ISSN:.
    OBJECTIVE: The present study assessed whether exhaled breath analysis using Selected Ion Flow Tube Mass Spectrometry could distinguish esophageal and gastric adenocarcinoma from noncancer controls. BACKGROUND: The majority of patients with upper gastrointestinal cancer present with advanced disease, resulting in poor long-term survival rates. Novel methods are needed to diagnose potentially curable upper gastrointestinal malignancies. METHODS: A Profile-3 Selected Ion Flow Tube Mass Spectrometry instrument was used for analysis of volatile organic compounds (VOCs) within exhaled breath samples. All study participants had undergone upper gastrointestinal endoscopy on the day of breath sampling. Receiver operating characteristic analysis and a diagnostic risk prediction model were used to assess the discriminatory accuracy of the identified VOCs. RESULTS: Exhaled breath samples were analyzed from 81 patients with esophageal (N = 48) or gastric adenocarcinoma (N = 33) and 129 controls including Barrett's metaplasia (N = 16), benign upper gastrointestinal diseases (N = 62), or a normal upper gastrointestinal tract (N = 51). Twelve VOCs-pentanoic acid, hexanoic acid, phenol, methyl phenol, ethyl phenol, butanal, pentanal, hexanal, heptanal, octanal, nonanal, and decanal-were present at significantly higher concentrations (P < 0.05) in the cancer groups than in the noncancer controls. The area under the ROC curve using these significant VOCs to discriminate esophageal and gastric adenocarcinoma from those with normal upper gastrointestinal tracts was 0.97 and 0.98, respectively. The area under the ROC curve for the model and validation subsets of the diagnostic prediction model was 0.92 ± 0.01 and 0.87 ± 0.03, respectively. CONCLUSIONS: Distinct exhaled breath VOC profiles can distinguish patients with esophageal and gastric adenocarcinoma from noncancer controls.

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  2. Qiongdan Xu, Xiaoyu Hu, Lei Zhong, Zelin Wang, Huayong Zhao, Jia Fu, Dongdong Cao, Liu Liu, Yan Zhang, Jianlei Lang. Advancements in Noninvasive Volatile Organic Compound Detection: Integrating Stirling Cooling Preconcentration with GC-FID/MS for Quantitative Breath Analysis. ACS Omega 2025, 10 (13) , 13694-13700. https://doi.org/10.1021/acsomega.5c01166
  3. Adrián Fernández-Lodeiro, Marios Constantinou, Christoforos Panteli, Agapios Agapiou, Chrysafis Andreou. Breath Analysis via Surface Enhanced Raman Spectroscopy. ACS Sensors 2025, 10 (2) , 602-621. https://doi.org/10.1021/acssensors.4c02685
  4. Benjamin M. Gordon, Jaisree Iyer, Christopher A. Harvey, Daniel A. Mew, Karly D. Knox, Susan A. Carroll, Sarah C. Chinn, Steven A. Hawks. Improving VOC Quantitation Methodology Using Selected Ion Flow Tube Mass Spectrometry. ACS ES&T Air 2025, 2 (2) , 277-285. https://doi.org/10.1021/acsestair.4c00263
  5. Benjamin M. Gordon, Jaisree Iyer, Kathlyn L. Baron, Taylor M. Bryson, Chris A. Harvey, Daniel A. Mew, Sarah C. Chinn, Susan A. Carroll, Steven A. Hawks. Determining the Outgassing Kinetics of a Cryo-Milled Polymer Using Temperature-Programmed Desorption SIFT-MS. ACS ES&T Air 2024, 1 (8) , 927-934. https://doi.org/10.1021/acsestair.4c00081
  6. Claire A. Batty, Victoria K. Pearson, Karen Olsson-Francis, Geraint Morgan. Volatile organic compounds (VOCs) in terrestrial extreme environments: implications for life detection beyond Earth. Natural Product Reports 2025, 42 (1) , 93-112. https://doi.org/10.1039/D4NP00037D
  7. Vaughan S. Langford, Mark J. Perkins. Improved volatiles analysis workflows using automated selected ion flow tube mass spectrometry (SIFT-MS). Analytical Methods 2024, 16 (47) , 8119-8138. https://doi.org/10.1039/D4AY01707B
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Cite this: Anal. Chem. 2024, 96, 4, 1397–1401
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https://doi.org/10.1021/acs.analchem.3c04286
Published January 20, 2024

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  • Abstract

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    Figure 1

    Figure 1. Novel interface designed for the coupling of TD and SIFT.

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    Figure 2

    Figure 2. Raw desorption profile of the 21 compounds included in the analytical method, the five compounds monitored for quality purpose and humidity.

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  • References

    This article references 23 other publications.

    1. 1
      Belluomo, I.; Boshier, P. R.; Myridakis, A.; Vadhwana, B.; Markar, S. R.; Spanel, P.; Hanna, G. B. Selected ion flow tube mass spectrometry for targeted analysis of volatile organic compounds in human breath. Nat. Protoc 2021, 16 (7), 3419– 3438,  DOI: 10.1038/s41596-021-00542-0
      1
      Selected ion flow tube mass spectrometry for targeted analysis of volatile organic compounds in human breath
      Belluomo, Ilaria; Boshier, Piers R.; Myridakis, Antonis; Vadhwana, Bhamini; Markar, Sheraz R.; Spanel, Patrik; Hanna, George B.
      Nature Protocols (2021), 16 (7), 3419-3438CODEN: NPARDW; ISSN:1750-2799. (Nature Portfolio)
      The anal. of volatile org. compds. (VOCs) within breath for noninvasive disease detection and monitoring is an emergent research field that has the potential to reshape current clin. practice. However, adoption of breath testing has been limited by a lack of standardization. This protocol provides a comprehensive workflow for online and offline breath anal. using selected ion flow tube mass spectrometry (SIFT-MS). Following the suggested protocol, 50 human breath samples can be analyzed and interpreted in <3 h. Key advantages of SIFT-MS are exploited, including the acquisition of real-time results and direct compd. quantification without need for calibration curves. The protocol includes details of methods developed for targeted anal. of disease-specific VOCs, specifically short-chain fatty acids, aldehydes, phenols, alcs. and alkanes. A procedure to make custom breath collection bags is also described. This standardized protocol for VOC anal. using SIFT-MS is intended to provide a basis for wider application and the use of breath anal. in clin. studies.
    2. 2
      Ajibola, O. A.; Smith, D.; Spanel, P.; Ferns, G. A. Effects of dietary nutrients on volatile breath metabolites. J. Nutr Sci. 2013, 2, e34  DOI: 10.1017/jns.2013.26
      2
      Effects of dietary nutrients on volatile breath metabolites
      Ajibola, Olawunmi A.; Smith, David; Spanel, Patrik; Ferns, Gordon A. A.
      Journal of Nutritional Science (2013), 2 (), e34/1-e34/15CODEN: JNSOAI; ISSN:2048-6790. (Cambridge University Press)
      A review. Breath anal. is becoming increasingly established as a means of assessing metabolic, biochem. and physiol. function in health and disease. The methods available for these analyses exploit a variety of complex physicochem. principles, but are becoming more easily utilized in the clin. setting. While some of the factors accounting for the biol. variation in breath metabolite concns. have been clarified, there has been relatively little work on the dietary factors that may influence them. In applying breath anal. to the clin. setting, it will be important to consider how these factors may affect the interpretation of endogenous breath compn. Diet may have complex effects on the generation of breath compds. These effects may either be due to a direct impact on metab., or because they alter the gastrointestinal flora. Bacteria are a major source of compds. in breath, and their generation of H2, hydrogen cyanide, aldehydes and alkanes may be an indicator of the health of their host.
    3. 3
      Spanel, P.; Smith, D. Progress in SIFT-MS: breath analysis and other applications. Mass Spectrom Rev. 2011, 30 (2), 236– 267,  DOI: 10.1002/mas.20303
      3
      Progress in SIFT-MS: breath analysis and other applications
      Spanel, Patrik; Smith, David
      Mass Spectrometry Reviews (2011), 30 (2), 236-267CODEN: MSRVD3; ISSN:0277-7037. (John Wiley & Sons, Inc.)
      A review. The development of selected ion flow tube mass spectrometry, SIFT-MS, is described from its inception as the modified very large SIFT instruments used to demonstrate the feasibility of SIFT-MS as an anal. technique, towards the smaller but bulky transportable instruments and finally to the current smallest Profile 3 instruments that have been located in various places, including hospitals and schools to obtain online breath analyses. The essential physics and engineering principles are discussed, which must be appreciated to design and construct a SIFT-MS instrument. The versatility and sensitivity of the Profile 3 instrument is illustrated by typical mass spectra obtained using the three precursor ions H3O+, NO+ and O2+·, and the need to account for differential ionic diffusion and mass discrimination in the anal. algorithms is emphasized to obtain accurate trace gas analyses. The performance of the Profile 3 instrument is illustrated by the results of several pilot studies, including (i) online real time quantification of several breath metabolites for cohorts of healthy adults and children, which have provided representative concn./population distributions, and the comparative analyses of breath exhaled via the mouth and nose that identify systemic and orally-generated compds., (ii) the enhancement of breath metabolites by drug ingestion, (iii) the identification of HCN as a marker of Pseudomonas colonization of the airways and (iv) emission of volatile compds. from urine, esp. ketone bodies, and from skin. Some very recent developments are discussed, including the quantification of carbon dioxide in breath and the combination of SIFT-MS with GC and ATD, and their significance. Finally, prospects for future SIFT-MS developments are alluded to.
    4. 4
      Sharma, A.; Kumar, R.; Varadwaj, P. Smelling the Disease: Diagnostic Potential of Breath Analysis. Mol. Diagn Ther 2023, 27 (3), 321– 347,  DOI: 10.1007/s40291-023-00640-7
      4
      Smelling the Disease: Diagnostic Potential of Breath Analysis
      Sharma Anju; Varadwaj Pritish; Kumar Rajnish
      Molecular diagnosis & therapy (2023), 27 (3), 321-347 ISSN:.
      Breath analysis is a relatively recent field of research with much promise in scientific and clinical studies. Breath contains endogenously produced volatile organic components (VOCs) resulting from metabolites of ingested precursors, gut and air-passage bacteria, environmental contacts, etc. Numerous recent studies have suggested changes in breath composition during the course of many diseases, and breath analysis may lead to the diagnosis of such diseases. Therefore, it is important to identify the disease-specific variations in the concentration of breath to diagnose the diseases. In this review, we explore methods that are used to detect VOCs in laboratory settings, VOC constituents in exhaled air and other body fluids (e.g., sweat, saliva, skin, urine, blood, fecal matter, vaginal secretions, etc.), VOC identification in various diseases, and recently developed electronic (E)-nose-based sensors to detect VOCs. Identifying such VOCs and applying them as disease-specific biomarkers to obtain accurate, reproducible, and fast disease diagnosis could serve as an alternative to traditional invasive diagnosis methods. However, the success of VOC-based identification of diseases is limited to laboratory settings. Large-scale clinical data are warranted for establishing the robustness of disease diagnosis. Also, to identify specific VOCs associated with illness states, extensive clinical trials must be performed using both analytical instruments and electronic noses equipped with stable and precise sensors.
    5. 5
      Markar, S. R.; Wiggins, T.; Antonowicz, S.; Chin, S. T.; Romano, A.; Nikolic, K.; Evans, B.; Cunningham, D.; Mughal, M.; Lagergren, J.; Hanna, G. B. Assessment of a Noninvasive Exhaled Breath Test for the Diagnosis of Oesophagogastric Cancer. JAMA Oncol 2018, 4 (7), 970– 976,  DOI: 10.1001/jamaoncol.2018.0991
      5
      Assessment of a Noninvasive Exhaled Breath Test for the Diagnosis of Oesophagogastric Cancer
      Markar Sheraz R; Wiggins Tom; Antonowicz Stefan; Chin Sung-Tong; Romano Andrea; Hanna George B; Nikolic Konstantin; Evans Benjamin; Cunningham David; Mughal Muntzer; Lagergren Jesper; Lagergren Jesper
      JAMA oncology (2018), 4 (7), 970-976 ISSN:.
      Importance: Early esophagogastric cancer (OGC) stage presents with nonspecific symptoms. Objective: The aim of this study was to determine the accuracy of a breath test for the diagnosis of OGC in a multicenter validation study. Design, Setting, and Participants: Patient recruitment for this diagnostic validation study was conducted at 3 London hospital sites, with breath samples returned to a central laboratory for selected ion flow tube mass spectrometry (SIFT-MS) analysis. Based on a 1:1 cancer:control ratio, and maintaining a sensitivity and specificity of 80%, the sample size required was 325 patients. All patients with cancer were on a curative treatment pathway, and patients were recruited consecutively. Among the 335 patients included; 172 were in the control group and 163 had OGC. Interventions: Breath samples were collected using secure 500-mL steel breath bags and analyzed by SIFT-MS. Quality assurance measures included sampling room air, training all researchers in breath sampling, regular instrument calibration, and unambiguous volatile organic compounds (VOCs) identification by gas chromatography mass spectrometry. Main Outcomes and Measures: The risk of cancer was identified based on a previously generated 5-VOCs model and compared with histopathology-proven diagnosis. Results: Patients in the OGC group were older (median [IQR] age 68 [60-75] vs 55 [41-69] years) and had a greater proportion of men (134 [82.2%]) vs women (81 [47.4%]) compared with the control group. Of the 163 patients with OGC, 123 (69%) had tumor stage T3/4, and 106 (65%) had nodal metastasis on clinical staging. The predictive probabilities generated by this 5-VOCs diagnostic model were used to generate a receiver operator characteristic curve, with good diagnostic accuracy, area under the curve of 0.85. This translated to a sensitivity of 80% and specificity of 81% for the diagnosis of OGC. Conclusions and Relevance: This study shows the potential of breath analysis in noninvasive diagnosis of OGC in the clinical setting. The next step is to establish the diagnostic accuracy of the test among the intended population in primary care where the test will be applied.
    6. 6
      Woodfield, G.; Belluomo, I.; Laponogov, I.; Veselkov, K.; Group, C. W.; Cross, A. J.; Hanna, G. B.; Boshier, P. R.; Lin, G. P.; Myridakis, A. Diagnostic performance of a non-invasive breath test for colorectal cancer: COBRA1 study. Gastroenterology 2022, 163, 1447,  DOI: 10.1053/j.gastro.2022.06.084
      6
      Diagnostic Performance of a Noninvasive Breath Test for Colorectal Cancer: COBRA1 Study
      Woodfield, Georgia; Belluomo, Ilaria; Laponogov, Ivan; Veselkov, Kirill; Cross, Amanda J.; Hanna, George B.
      Gastroenterology (2022), 163 (5), 1447-1449.e8CODEN: GASTAB; ISSN:0016-5085. (Elsevier Inc.)
      An intermediate triage test to identify patients at risk of Colorectal Cancer could streamline referral pathways. The target sample size was 1463 patients (117 CRC, 1346 control subjects) using the power diagnostic test function from the MKmisc R package, considering type I error (alpha) of 0.05, power (1-beta) of 0.8, prevalence value of 0.08, and assumed difference of 0.1. The study recruited patients aged 18-90 years attending 7 London hospitals for a bowel cancer screening program colonoscopy because of a pos. fecal occult blood test (n 664), colonoscopy for other indications (n 645), or surgical colorectal adenocarcinoma resection (n 123) (June 2017 to Feb. 2020). Included in the anal. were 1432 patients (828 men), with a median age of 66.5 years (range, 18-90). No adverse events were reported. Of 1432 patients, 357 had a normal colonoscopy; 188 had benign pathol. (hemorrhoids or diverticular disease); 106 had inflammatory bowel disease; 348, 67, and 204 patients had low-, intermediate- and highrisk polyps, resp.; and 162 had colorectal adenocarcinoma.
    7. 7
      Kamal, F.; Kumar, S.; Edwards, M. R.; Veselkov, K.; Belluomo, I.; Kebadze, T.; Romano, A.; Trujillo-Torralbo, M. B.; Shahridan Faiez, T.; Walton, R. Virus-induced Volatile Organic Compounds Are Detectable in Exhaled Breath during Pulmonary Infection. Am. J. Respir Crit Care Med. 2021, 204 (9), 1075– 1085,  DOI: 10.1164/rccm.202103-0660OC
      7
      Virus-induced volatile organic compounds are detectable in exhaled breath during pulmonary infection
      Kamal, Faisal; Kumar, Sacheen; Edwards, Michael R.; Veselkov, Kirill; Belluomo, Ilaria; Kebadze, Tatiana; Romano, Andrea; Trujillo-Torralbo, Maria-Belen; Faiez, Tasnim Shahridan; Walton, Ross; Ritchie, Andrew I.; Wiseman, Dexter J.; Laponogov, Ivan; Donaldson, Gavin; Wedzicha, Jadwiga A.; Johnston, Sebastian L.; Singanayagam, Aran; Hanna, George B.
      American Journal of Respiratory and Critical Care Medicine (2021), 204 (9), 1075-1085CODEN: AJCMED; ISSN:1073-449X. (American Thoracic Society)
      Chronic obstructive pulmonary disease (COPD) is a condition punctuated by acute exacerbations commonly triggered by viral and/or bacterial infection. Early identification of exacerbation triggers is important to guide appropriate therapy, but currently available tests are slow and imprecise. Volatile org. compds. (VOCs) can be detected in exhaled breath and have the potential to be rapid tissue-specific biomarkers of infection etiol. Objectives: To det. whether volatile org. compd. measurement could distinguish viral from bacterial infection in COPD. We used serial sampling within in vitro and in vivo studies to elucidate the dynamic changes that occur in VOC prodn. during acute respiratory viral infection. Highly sensitive gas chromatog.-mass spectrometry techniques were used to measure VOC prodn. from infected airway epithelial-cell cultures and in exhaled breath samples from healthy subjects exptl. challenged with rhinovirus (RV)-A16 and from subjects with COPD with naturally occurring exacerbations. Measurements and Main Results: We identified a novel VOC signature comprising decane and other long-chain alkane compds. that is induced during RV infection of cultured airway epithelial cells and is also increased in the exhaled breath from healthy subjects exptl. challenged with RV and from patients with COPD during naturally occurring viral exacerbations. These compds. correlated with the magnitude of antiviral immune responses, viral burden, and exacerbation severity but were not induced by bacterial infection, suggesting that they represent a specific virus-inducible signature. Our study highlights the potential for measurement of exhaled breath VOCs as rapid, noninvasive biomarkers of viral infection. Further studies are needed to det. whether measurement of these signatures could be used to guide more targeted therapy with antibiotic/antiviral agents for COPD exacerbations.
    8. 8
      Woodfield, G.; Belluomo, I.; Boshier, P. R.; Waller, A.; Fayyad, M.; von Wagner, C.; Cross, A. J.; Hanna, G. B. Feasibility and acceptability of breath research in primary care: a prospective, cross-sectional, observational study. BMJ. Open 2021, 11 (4), e044691  DOI: 10.1136/bmjopen-2020-044691
      There is no corresponding record for this reference.
    9. 9
      Weber, R.; Haas, N.; Baghdasaryan, A.; Bruderer, T.; Inci, D.; Micic, S.; Perkins, N.; Spinas, R.; Zenobi, R.; Moeller, A. Volatile organic compound breath signatures of children with cystic fibrosis by real-time SESI-HRMS. ERJ. Open Res. 2020, 6 (1), 00171-2019,  DOI: 10.1183/23120541.00171-2019
      There is no corresponding record for this reference.
    10. 10
      Bruderer, T.; Gaisl, T.; Gaugg, M. T.; Nowak, N.; Streckenbach, B.; Muller, S.; Moeller, A.; Kohler, M.; Zenobi, R. On-Line Analysis of Exhaled Breath Focus Review. Chem. Rev. 2019, 119 (19), 10803– 10828,  DOI: 10.1021/acs.chemrev.9b00005
      10
      On-Line Analysis of Exhaled Breath
      Bruderer, Tobias; Gaisl, Thomas; Gaugg, Martin T.; Nowak, Nora; Streckenbach, Bettina; Muller, Simona; Moeller, Alexander; Kohler, Malcolm; Zenobi, Renato
      Chemical Reviews (Washington, DC, United States) (2019), 119 (19), 10803-10828CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. Online anal. of exhaled breath offers insight into a person's metab. without the need for sample prepn. or sample collection. Due to its noninvasive nature and the possibility to sample continuously, the anal. of breath has great clin. potential. The unique features of this technol. make it an attractive candidate for applications in medicine, beyond the task of diagnosis. The authors review the current methodologies for online breath anal., discuss current and future applications, and critically evaluate challenges and pitfalls such as the need for standardization. Special emphasis is given to the use of the technol. in diagnosing respiratory diseases, potential niche applications, and the promise of breath anal. for personalized medicine. The anal. methodologies used range from very small and low-cost chem. sensors, which are ideal for continuous monitoring of disease status, to optical spectroscopy and state-of-the-art, high-resoln. mass spectrometry. The latter can be used for untargeted anal. of exhaled breath, with the capability to identify hitherto unknown mols. The interpretation of the resulting big data sets is complex and often constrained due to a limited no. of participants. Even larger data sets will be needed for assessing reproducibility and for validation of biomarker candidates. In addn., mol. structures and quantification of compds. are generally not easily available from online measurements and require complementary measurements, for example, a sepn. method coupled to mass spectrometry. Furthermore, a lack of standardization still hampers the application of the technique to screen larger cohorts of patients. This review summarizes the present status and continuous improvements of the principal online breath anal. methods and evaluates obstacles for their wider application.
    11. 11
      Harshman, S. W.; Mani, N.; Geier, B. A.; Kwak, J.; Shepard, P.; Fan, M.; Sudberry, G. L.; Mayes, R. S.; Ott, D. K.; Martin, J. A.; Grigsby, C. C. Storage stability of exhaled breath on Tenax TA. J. Breath Res. 2016, 10 (4), 046008,  DOI: 10.1088/1752-7155/10/4/046008
      11
      Storage stability of exhaled breath on Tenax TA
      Harshman, Sean W.; Mani, Nilan; Geier, Brian A.; Kwak, Jae; Shepard, Phillip; Fan, Maomian; Sudberry, Gregory L.; Mayes, Ryan S.; Ott, Darrin K.; Martin, Jennifer A.; Grigsby, Claude C.
      Journal of Breath Research (2016), 10 (4), 046008/1-046008/12CODEN: JBROBW; ISSN:1752-7155. (IOP Publishing Ltd.)
      Exhaled breath is coming to the forefront of non-invasive biomarker discovery efforts. Concn. of exhaled breath volatile org. compds. (VOCs) on thermal desorption (TD) tubes with subsequent anal. by gas chromatog.-mass spectrometry (GC-MS) has dominated this field. As discovery experimentation increases in frequency, the need to evaluate the long-term storage stability of exhaled breath VOCs on thermal desorption adsorbent material is crit. To address this gap, exhaled breath was loaded on Tenax TA thermal desorption tubes and stored at various temp. conditions. 74 VOCs, 56 of which have been previously uncharacterized, were monitored using GC-MS over a period of 31 d. The results suggest that storage of exhaled breath at cold temps. (4 °C) provides the most consistent retention of exhaled breath VOCs temporally. Samples were detd. to be stable up to 14 d across storage conditions prior to gaining or losing 1-2 std. deviations in abundance. Through gene set enrichment anal. (GSEA), certain chem. classes were found to be pos. (acids) or neg. (sulfur-contg.) enriched temporally. By means of field sample collections, the effect of storage and shipping was found to be similar to those studies preformed in the lab. at 4 °C. Collectively this study not only provides recommendations for proper storage conditions and storage length, but also illustrates the use of GSEA to exhaled breath based GC-MS data.
    12. 12
      Kang, S.; Paul Thomas, C. L. How long may a breath sample be stored for at −80 degrees C? A study of the stability of volatile organic compounds trapped onto a mixed Tenax:Carbograph trap adsorbent bed from exhaled breath. J. Breath Res. 2016, 10 (2), 026011,  DOI: 10.1088/1752-7155/10/2/026011
      12
      How long may a breath sample be stored for at -80 °C? A study of the stability of volatile organic compounds trapped onto a mixed Tenax:Carbograph trap adsorbent bed from exhaled breath
      Kang, S.; Paul Thomas, C. L.
      Journal of Breath Research (2016), 10 (2), 026011/1-026011/11CODEN: JBROBW; ISSN:1752-7155. (IOP Publishing Ltd.)
      Thermal desorption is used extensively in exhaled breath volatile org. compd. (VOC) anal., and it is often necessary to store the adsorbent tube samples before anal. The possible introduction of storage artifacts is an important potential confounding factor in the development of std. methodologies for breath sampling and anal. The stability of VOCs trapped from breath samples onto a dual bed Tenax TA:Carbograph adsorbent tube and stored °80°C was studied over 12.5 mo. 25 samples were collected from a single male participant over 3h and then stored at °80 °C. Randomly selected adsorbent tubes were subsequent analyzed by thermal desorption-gas chromatog.-mass spectrometry at 5 times points throughout the 12.5 mo of the study. Toluene-d8, decane-d22 and hexadecane-d34 internal stds. were used to manage the instrument variability throughout the duration of the study. A breath-matrix consisting of 161 endogenous and 423 exogenous VOC was created. Iterative orthogonal partial least squared discriminant anal. (OPLS-DA) and principal components anal. (PCA) indicated that it was not possible to detect storage artifacts at 1.5 mo storage. By 6 mo storage artifacts were discernible with significant changes obsd. for 27% of the recovered VOC. Endogenous VOC were obsd. to be more susceptible to storage. A paired two-tailed t-test on the endogenous compds. indicated that the max. storage duration under these conditions was 1.5 mo with 94% of the VOCs stable. This study indicates that a prudent approach is best adopted for the storage of adsorbent samples; storage times should be minimised, and storage time examd. as a possible discriminatory factor in multivariate anal.
    13. 13
      Stefanuto, P. H.; Zanella, D.; Vercammen, J.; Henket, M.; Schleich, F.; Louis, R.; Focant, J. F. Multimodal combination of GC x GC-HRTOFMS and SIFT-MS for asthma phenotyping using exhaled breath. Sci. Rep 2020, 10 (1), 16159,  DOI: 10.1038/s41598-020-73408-2
      13
      Multimodal combination of GC x GC-HRTOFMS and SIFT-MS for asthma phenotyping using exhaled breath
      Stefanuto, Pierre-Hugues; Zanella, Delphine; Vercammen, Joeri; Henket, Monique; Schleich, Florence; Louis, Renaud; Focant, Jean-Francois
      Scientific Reports (2020), 10 (1), 16159CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
      Chronic inflammatory lung diseases impact more than 300 million of people worldwide. Because they are not curable, these diseases have a high impact on both the quality of life of patients and the healthcare budget. The stability of patient condition relies mostly on const. treatment adaptation and lung function monitoring. However, due to the variety of inflammation phenotypes, almost one third of the patients receive an ineffective treatment. To improve phenotyping, we evaluated the complementarity of two techniques for exhaled breath anal.: full resolving comprehensive two-dimensional gas chromatog. coupled to high-resoln. time-of-flight mass spectrometry (GC x GC-HRTOFMS) and rapid screening selected ion flow tube MS (SIFT-MS). GC x GC-HRTOFMS has a high resolving power and offers a full overview of sample compn., providing deep insights on the ongoing biol. SIFT-MS is usually used for targeted analyses, allowing rapid classification of samples in defined groups. In this study, we used SIFT-MS in a possible untargeted full-scan mode, where it provides pattern-based classification capacity. We analyzed the exhaled breath of 50 asthmatic patients. Both techniques provided good classification accuracy (around 75%), similar to the efficiency of other clin. tools routinely used for asthma phenotyping. Moreover, our study provides useful information regarding the complementarity of the two techniques.
    14. 14
      Hryniuk, A.; Ross, B. M. Detection of acetone and isoprene in human breath using a combination of thermal desorption and selected ion flow tube mass spectrometry. Int. J. Mass Spectrom. 2009, 285 (1–2), 26– 30,  DOI: 10.1016/j.ijms.2009.02.027
      14
      Detection of acetone and isoprene in human breath using a combination of thermal desorption and selected ion flow tube mass spectrometry
      Hryniuk, Alexa; Ross, Brian M.
      International Journal of Mass Spectrometry (2009), 285 (1-2), 26-30CODEN: IMSPF8; ISSN:1387-3806. (Elsevier B.V.)
      The measurement of volatile chems. in human exhalant (breath anal.) has recently emerged as a non-invasive technique with the potential for the early diagnosis of disease. A common method of volatile chem. collection is to capture gases onto a solid phase sorbent followed, at a later time, by thermal release and anal. This technique, termed thermal desorption (TD), may be a useful means to collect and store breath volatiles in a clin. setting prior to anal. TD is, however, normally used in conjunction with gas chromatog. (TD-GC) which results in slow anal. times and the required use of chem. stds. The new technique of selected ion flow tube mass spectrometry (SIFT-MS) offers a more rapid anal. process without the need for stds. SIFT-MS is normally used to analyze gas concn. in real-time and it is unclear whether combined TD and SIFT-MS can be successfully employed for breath anal. We found that there was an approx. 1 to 1 concordance between levels of isoprene or acetone in the breath of 12 healthy volunteers measured either using real-time SIFT-MS or offline using a combination of SIFT-MS and TD (TD-SIFT-MS). The use of higher vols. of human breath did impact TD-SIFT-MS measurements of isoprene (but not acetone) with an apparent ceiling effect being obsd. Nevertheless our findings demonstrate the potential for breath anal. using a combination of TD and SIFT-MS, an approach which may find utility in a clin. setting which does not allow online anal. of breath.
    15. 15
      Sovova, K.; Spesyvyi, A.; Bursova, M.; Pasztor, P.; Kubista, J.; Shestivska, V.; Spanel, P. Time-integrated thermal desorption for quantitative SIFT-MS analyses of atmospheric monoterpenes. Anal. Bioanal. Chem. 2019, 411 (14), 2997– 3007,  DOI: 10.1007/s00216-019-01782-6
      15
      Time-integrated thermal desorption for quantitative SIFT-MS analyses of atmospheric monoterpenes
      Sovova, Kristyna; Spesyvyi, Anatolii; Bursova, Miroslava; Pasztor, Pavel; Kubista, Jiri; Shestivska, Violetta; Spanel, Patrik
      Analytical and Bioanalytical Chemistry (2019), 411 (14), 2997-3007CODEN: ABCNBP; ISSN:1618-2642. (Springer)
      A new time-integrated thermal desorption technique has been developed that can be used with selected ion flow tube mass spectrometry, TI-TD/SIFT-MS, for off-line quant. analyses of VOCs accumulated onto sorbents. Using a slow desorption temp. ramp, the abs. amts. of desorbed compds. can be quantified in real time by SIFT-MS and constitutional isomers can be sepd. To facilitate application of this technique to environmental atm. monitoring, method parameters were optimized for quantification of the three common atm. monoterpenes: β-pinene, R-limonene and 3-carene. Three sorbent types, Tenax TA, Tenax GR and Porapak Q, were tested under 26 different desorption conditions detd. by the "design of expt.", DOE, systematic approach. The optimal combination of type of sorbent, bed length, sampling flow rate, sample vol. and the initial desorption temp. was detd. from the exptl. results by ANOVA. Porapak Q exhibited better efficiency of sample collection and further extn. for total monoterpene concn. measurements. However, Tenax GR or TA enabled sepn. of all three monoterpenes. The results of this lab. study were tested with the sample accumulated from a branch of a Pinus nigra tree.
    16. 16
      Slingers, G.; Eede, M. V.; Lindekens, J.; Spruyt, M.; Goelen, E.; Raes, M.; Koppen, G. Real-time versus thermal desorption selected ion flow tube mass spectrometry for quantification of breath volatiles. Rapid Commun. Mass Spectrom. 2021, 35 (4), e8994,  DOI: 10.1002/rcm.8994
      16
      Real-time versus thermal desorption selected ion flow tube mass spectrometry for quantification of breath volatiles
      Slingers, Gitte; Vanden Eede, Martin; Lindekens, Jill; Spruyt, Maarten; Goelen, Eddy; Raes, Marc; Koppen, Gudrun
      Rapid Communications in Mass Spectrometry (2021), 35 (4), e8994CODEN: RCMSEF; ISSN:0951-4198. (John Wiley & Sons Ltd.)
      Rationale : Selected ion flow tube mass spectrometry (SIFT-MS) is versatile, rapidly provides result output and dets. a wide range of volatiles, making it suitable for biomedical applications. When direct sampling into the SIFT-MS instrument is impractical, combining thermal desorption (TD) and SIFT-MS might offer a soln. as it allows sample storage on sorbent tubes for later anal. This work compares off-line TD SIFT-MS and real-time SIFT-MS for the quantification of selected breath volatiles. Methods : Ten healthy non-smoking individuals provided 60 breath samples per method. For off-line anal., breath was collected onto sorbent tubes via a breath sampler provided with filtered inspiratory air. After TD, samples were re-collected in Tedlar bags which were then connected to the SIFT-MS instrument. For real-time anal., breath was sampled directly into the instrument. In both cases the anal. method included a total of 155 product ions, and 14 selected volatiles were quantified. The agreement between the methods was assessed using Pearson correlation coeffs. and Bland-Altman plots. Results : Overall, correlations between real-time and off-line anal. were moderate to very strong (r = 0.43-0.92) depending on the volatile of interest, except for 2,3-butanedione and styrene. The difference between real-time and off-line measured breath concns. (av. bias) ranged between -14.57 and 20.48 ppbv. For acetone and isoprene, it was 251.53 and 31.9 ppbv, resp. Conclusions : Real-time SIFT-MS and off-line TD SIFT-MS for quantification of selected breath volatiles did not show optimal agreement. Analyzing a multitude of analytes in breath via direct exhalation into a SIFT-MS instrument for real-time anal. is challenging. On the other hand, off-line anal. using a breath collection device also has its issues such as possible sample losses due to selective absorption depending on the sorbent used or during desorption and transfer to the instrument. Despite these drawbacks, both methods were moderately well correlated.
    17. 17
      EMA. Guideline on bioanalytical method validation. European Medical Agency 2012, 58 (3), 284– 289.
      There is no corresponding record for this reference.
    18. 18
      Smith, D.; Spanel, P.; Demarais, N.; Langford, V. S.; McEwan, M. J. Recent developments and applications of selected ion flow tube mass spectrometry (SIFT-MS). Mass Spectrom Rev. 2023, e21835  DOI: 10.1002/mas.21835
      There is no corresponding record for this reference.
    19. 19
      Spanel, P.; Dryahina, K.; Smith, D. A general method for the calculation of absolute trace gas concentrations in air and breath from selected ion flow tube mass spectrometry data. Int. J. Mass Spectrom. 2006, 249, 230– 239,  DOI: 10.1016/j.ijms.2005.12.024
      19
      A general method for the calculation of absolute trace gas concentrations in air and breath from selected ion flow tube mass spectrometry data
      Spanel, Patrik; Dryahina, Kseniya; Smith, David
      International Journal of Mass Spectrometry (2006), 249/250 (), 230-239CODEN: IMSPF8; ISSN:1387-3806. (Elsevier B.V.)
      A complete description is presented of a numerical method that allows the calcn., in real time, of abs. concns. of trace gases, including volatile org. compds. and water vapor, from selected ion flow tube mass spectrometry, SIFT-MS, data. No assumptions are made concerning the SIFT-MS instrument size or its configuration and thus the calcn. can be applied to the currently available, relatively large instruments and the anticipated new generation of smaller SIFT-MS instruments. This numerical method clearly distinguishes those parameters that are obviously specific to a particular instrument, including flow tube geometry, degree of mass discrimination in the anal. mass spectrometer and flow tube reaction time, from general fundamental processes, in particular the differential diffusive loss of ions along the flow tube that is dependent on the properties of those ions involved in the detn. of the concns. of particular trace gases. The essential reaction and transport kinetics are outlined, which describe the formation and loss of the product ions formed in the chem. ionization of the trace gases by the precursor ions. A generalized calcn. of the required ionic diffusion coeffs. is introduced with options either for their accurate detn. from the mol. geometry of ions or for less accurate but simpler ests. obtained using just the ionic mass. Based on the above ideas, a straightforward calcn. sequence is shown to det. trace gas concns. by SIFT-MS, and its utility demonstrated by an example of the anal. of acetone in exhaled breath.
    20. 20
      Drabinska, N.; Flynn, C.; Ratcliffe, N.; Belluomo, I.; Myridakis, A.; Gould, O.; Fois, M.; Smart, A.; Devine, T.; Costello, B. L. A literature survey of all volatiles from healthy human breath and bodily fluids: the human volatilome. J. Breath Res. 2021, 15 (3), 034001,  DOI: 10.1088/1752-7163/abf1d0
      There is no corresponding record for this reference.
    21. 21
      Behera, S. N.; Sharma, M.; Aneja, V. P.; Balasubramanian, R. Ammonia in the atmosphere: a review on emission sources, atmospheric chemistry and deposition on terrestrial bodies. Environ. Sci. Pollut Res. Int. 2013, 20 (11), 8092– 8131,  DOI: 10.1007/s11356-013-2051-9
      21
      Ammonia in the atmosphere: a review on emission sources, atmospheric chemistry and deposition on terrestrial bodies
      Behera Sailesh N; Sharma Mukesh; Aneja Viney P; Balasubramanian Rajasekhar
      Environmental science and pollution research international (2013), 20 (11), 8092-131 ISSN:.
      Gaseous ammonia (NH3) is the most abundant alkaline gas in the atmosphere. In addition, it is a major component of total reactive nitrogen. The largest source of NH3 emissions is agriculture, including animal husbandry and NH3-based fertilizer applications. Other sources of NH3 include industrial processes, vehicular emissions and volatilization from soils and oceans. Recent studies have indicated that NH3 emissions have been increasing over the last few decades on a global scale. This is a concern because NH3 plays a significant role in the formation of atmospheric particulate matter, visibility degradation and atmospheric deposition of nitrogen to sensitive ecosystems. Thus, the increase in NH3 emissions negatively influences environmental and public health as well as climate change. For these reasons, it is important to have a clear understanding of the sources, deposition and atmospheric behaviour of NH3. Over the last two decades, a number of research papers have addressed pertinent issues related to NH3 emissions into the atmosphere at global, regional and local scales. This review article integrates the knowledge available on atmospheric NH3 from the literature in a systematic manner, describes the environmental implications of unabated NH3 emissions and provides a scientific basis for developing effective control strategies for NH3.
    22. 22
      Spanel, P.; Spesyvyi, A.; Smith, D. Electrostatic Switching and Selection of H(3)O(+), NO(+), and O(2)(+*) Reagent Ions for Selected Ion Flow-Drift Tube Mass Spectrometric Analyses of Air and Breath. Anal. Chem. 2019, 91 (8), 5380– 5388,  DOI: 10.1021/acs.analchem.9b00530
      22
      Electrostatic Switching and Selection of H3O+, NO+, and O2+• Reagent Ions for Selected Ion Flow-Drift Tube Mass Spectrometric Analyses of Air and Breath
      Spanel, Patrik; Spesyvyi, Anatolii; Smith, David
      Analytical Chemistry (Washington, DC, United States) (2019), 91 (8), 5380-5388CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      Soft chem. ionization mass spectrometry techniques, particularly the well-established proton transfer reaction mass spectrometry, PTR-MS, and selected ion flow tube mass spectrometry, SIFT-MS, are widely used for real-time quantification of volatile org. compds. in ambient air and exhaled breath with applications ranging from environmental science to medicine. The most common reagent ions H3O+, NO+, or O2+• can be selected either by quadrupole mass filtering from a discharge ion source, which is relatively inefficient, or by switching the gas/vapor in the ion source, which is relatively slow. The chosen reagent ions are introduced into a flow tube or flow-drift tube reactor where they react with analyte mols. in sample gas. This article describes a new electrostatic reagent ion switching, ERIS, technique by which H3O+, NO+, and O2+• reagent ions, produced simultaneously in three sep. gas discharges, can be purified in post-discharge source drift tubes, switched rapidly, and selected for transport into a flow-drift tube reactor. The construction of the device and the ion-mol. chem. exploited to purify the individual reagent ions are described. The speed and sensitivity of ERIS coupled to a selected ion flow-drift tube mass spectrometry, SIFDT-MS, is demonstrated by the simultaneous quantification of methanol with H3O+, acetone with NO+, and di-Me sulfide with O2+• reagent ions in single breath exhalations. The present ERIS approach is preferable to the previously used quadrupole filtering, as it increases anal. sensitivity of the SIFDT-MS instrument while reducing its size and the required no. of vacuum pumps.
    23. 23
      Kumar, S.; Huang, J.; Abbassi-Ghadi, N.; Mackenzie, H. A.; Veselkov, K. A.; Hoare, J. M.; Lovat, L. B.; Spanel, P.; Smith, D.; Hanna, G. B. Mass Spectrometric Analysis of Exhaled Breath for the Identification of Volatile Organic Compound Biomarkers in Esophageal and Gastric Adenocarcinoma. Ann. Surg 2015, 262 (6), 981– 990,  DOI: 10.1097/SLA.0000000000001101
      23
      Mass Spectrometric Analysis of Exhaled Breath for the Identification of Volatile Organic Compound Biomarkers in Esophageal and Gastric Adenocarcinoma
      Kumar Sacheen; Huang Juzheng; Abbassi-Ghadi Nima; Mackenzie Hugh A; Veselkov Kirill A; Hoare Jonathan M; Lovat Laurence B; Spanel Patrik; Smith David; Hanna George B
      Annals of surgery (2015), 262 (6), 981-90 ISSN:.
      OBJECTIVE: The present study assessed whether exhaled breath analysis using Selected Ion Flow Tube Mass Spectrometry could distinguish esophageal and gastric adenocarcinoma from noncancer controls. BACKGROUND: The majority of patients with upper gastrointestinal cancer present with advanced disease, resulting in poor long-term survival rates. Novel methods are needed to diagnose potentially curable upper gastrointestinal malignancies. METHODS: A Profile-3 Selected Ion Flow Tube Mass Spectrometry instrument was used for analysis of volatile organic compounds (VOCs) within exhaled breath samples. All study participants had undergone upper gastrointestinal endoscopy on the day of breath sampling. Receiver operating characteristic analysis and a diagnostic risk prediction model were used to assess the discriminatory accuracy of the identified VOCs. RESULTS: Exhaled breath samples were analyzed from 81 patients with esophageal (N = 48) or gastric adenocarcinoma (N = 33) and 129 controls including Barrett's metaplasia (N = 16), benign upper gastrointestinal diseases (N = 62), or a normal upper gastrointestinal tract (N = 51). Twelve VOCs-pentanoic acid, hexanoic acid, phenol, methyl phenol, ethyl phenol, butanal, pentanal, hexanal, heptanal, octanal, nonanal, and decanal-were present at significantly higher concentrations (P < 0.05) in the cancer groups than in the noncancer controls. The area under the ROC curve using these significant VOCs to discriminate esophageal and gastric adenocarcinoma from those with normal upper gastrointestinal tracts was 0.97 and 0.98, respectively. The area under the ROC curve for the model and validation subsets of the diagnostic prediction model was 0.92 ± 0.01 and 0.87 ± 0.03, respectively. CONCLUSIONS: Distinct exhaled breath VOC profiles can distinguish patients with esophageal and gastric adenocarcinoma from noncancer controls.

  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.analchem.3c04286.

    • Calibration curves in different matrices (Figure S1); list of compounds included in the analytical method (Table S1); concentrations of each calibration curve point (Table S2); linearity, LOD, and LOQ obtained at Imperial College London and Syft Technologies (Table S3); accuracy and precision obtained at Imperial College London and Syft Technologies (Table S4) (PDF)


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