In recent decades, two facts have changed the opinion of researchers about the function of acetone in humans. Firstly, it has turned out that acetone cannot be regarded as simply a waste product of metabolism, because there are several pathways in which acetone is produced or broken down. Secondly, methods have emerged making possible its detection in exhaled breath, thereby offering an attractive alternative to investigation of blood and urine samples. From a clinical point of view the measurement of breath acetone levels is important, but there are limitations to its wide application. These limitations can be divided into two classes, technical and biological limits. The technical limits include the storage of samples, detection threshold, standardization of clinical settings, and the price of instruments. When considering the biological ranges of acetone, personal factors such as race, age, gender, weight, food consumption, medication, illicit drugs, and even profession/class have to be taken into account to use concentration information for disorders. In some diseases such as diabetes mellitus and lung cancer, as well as in nutrition-related behavior such as starvation and ketogenic diet, breath acetone has been extensively examined. At the same time, there is a lack of investigations in other cases in which ketosis is also evident, such as in alcoholism or an inborn error of metabolism. In summary, the detection of acetone in exhaled breath is a useful and promising tool for diagnosis and it can be used as a marker to follow the effectiveness of treatments in some disorders. However, further endeavors are needed for clarification of the exact distribution of acetone in different body compartments and evaluation of its complex role in humans, especially in those cases in which a ketotic state also occurs.
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ISSN: 1752-7163
This journal is dedicated to all aspects of breath science, with the major focus on analysis of exhaled breath in physiology and medicine, and the diagnosis and treatment of breath odours.
Official Journal of the International Association for Breath Research (IABR).
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Veronika Ruzsányi and Miklós Péter Kalapos 2017 J. Breath Res. 11 024002
Theo Issitt et al 2022 J. Breath Res. 16 024001
Volatile compounds contained in human breath reflect the inner workings of the body. A large number of studies have been published that link individual components of breath to disease, but diagnostic applications remain limited, in part due to inconsistent and conflicting identification of breath biomarkers. New approaches are therefore required to identify effective biomarker targets. Here, volatile organic compounds have been identified in the literature from four metabolically and physiologically distinct diseases and grouped into chemical functional groups (e.g. methylated hydrocarbons or aldehydes; based on known metabolic and enzymatic pathways) to support biomarker discovery and provide new insight on existing data. Using this functional grouping approach, principal component analysis doubled explanatory capacity from 19.1% to 38% relative to single individual compound approaches. Random forest and linear discriminant analysis reveal 93% classification accuracy for cancer. This review and meta-analysis provides insight for future research design by identifying volatile functional groups associated with disease. By incorporating our understanding of the complexities of the human body, along with accounting for variability in methodological and analytical approaches, this work demonstrates that a suite of targeted, functional volatile biomarkers, rather than individual biomarker compounds, will improve accuracy and success in diagnostic research and application.
Rohit Vadala et al 2023 J. Breath Res. 17 024002
Lung cancer is one of the common malignancies with high mortality rate and a poor prognosis. Most lung cancer cases are diagnosed at an advanced stage either due to limited resources of infrastructure, trained human resources, or delay in clinical suspicion. Low-dose computed tomography has emerged as a screening tool for lung cancer detection but this may not be a feasible option for most developing countries. Electronic nose is a unique non-invasive device that has been developed for lung cancer diagnosis and monitoring response by exhaled breath analysis of volatile organic compounds. The breath-print have been shown to differ not only among lung cancer and other respiratory diseases, but also between various types of lung cancer. Hence, we postulate that the breath-print analysis by electronic nose could be a potential biomarker for the early detection of lung cancer along with monitoring treatment response in a resource-limited setting. In this review, we have consolidated the current published literature suggesting the use of an electronic nose in the diagnosis and monitoring treatment response of lung cancer.
Julia Eichinger et al 2024 J. Breath Res. 18 036001
We explored appropriate technical setups for the detection of volatile organic compounds (VOCs) from exhaled cow breath by comparing six different polymer-based solid-phase extraction (SPE) cartridges currently on the market for gas chromatography/mass spectrometry (GC-MS) screening. Exhaled breath was sampled at a single timepoint from five lactating dairy cows using six different SPE cartridges (Bond Elut ENV (ENV); Chromabond HRX (HRX); Chromabond HRP (HRP); Chromabond HLB (HLB); Chromabond HR-XCW (XCW) and Chromabond HR-XAW (XAW)). The trapped VOCs were analyzed by dynamic headspace vacuum in-tube extraction GC-MS (DHS-V-ITEX-GC-MS). Depending on the SPE cartridge, we detected 1174–1312 VOCs per cartridge. Most VOCs were alkenes, alkanes, esters, ketones, alcohols, aldehydes, amines, nitriles, ethers, amides, carboxylic acids, alkynes, azoles, terpenes, pyridines, or sulfur-containing compounds. The six SPE cartridges differed in their specificity for the chemical compounds, with the XAW cartridge showing the best specificity for ketones. The greatest differences between the tested SPE cartridges appeared in the detection of specific VOCs. In total, 176 different VOCs were detected with a match factor >80%. The greatest number of specific VOCs was captured by XAW (149), followed by ENV (118), HLB (117), HRP (115), HRX (114), and XCW (114). We conclude that the tested SPE cartridges are suitable for VOC sampling from exhaled cow breath, but the SPE cartridge choice enormously affects the detected chemical groups and the number of detected VOCs. Therefore, an appropriate SPE adsorbent cartridge should be selected according to our proposed inclusion criteria. For targeted metabolomics approaches, the SPE cartridge choice depends on the VOCs or chemical compound groups of interest based on our provided VOC list. For untargeted approaches without information on the animals' metabolic condition, we suggest using multi-sorbent SPE cartridges or multiple cartridges per animal.
Om Prakash Singh et al 2018 J. Breath Res. 12 026003
The development of a human respiration carbon dioxide (CO2) measurement device to evaluate cardiorespiratory status inside and outside a hospital setting has proven to be a challenging area of research over the few last decades. Hence, we report a real-time, user operable CO2 measurement device using an infrared CO2 sensor (Arduino Mega2560) and a thin film transistor (TFT, 3.5''), incorporated with low pass (cut-off frequency, 10 Hz) and moving average (span, 8) filters. The proposed device measures features such as partial end-tidal carbon dioxide (EtCO2), respiratory rate (RR), inspired carbon dioxide (ICO2), and a newly proposed feature—Hjorth activity—that annotates data with the date and time from a real-time clock, and is stored onto a secure digital (SD) card. Further, it was tested on 22 healthy subjects and the performance (reliability, validity and relationship) of each feature was established using (1) an intraclass correlation coefficient (ICC), (2) standard error measurement (SEM), (3) smallest detectable difference (SDD), (4) Bland–Altman plot, and (5) Pearson's correlation (r). The SEM, SDD, and ICC values for inter- and intra-rater reliability were less than 5% and more than 0.8, respectively. Further, the Bland–Altman plot demonstrates that mean differences ± standard deviations for a set limit were 0.30 ± 0.77 mmHg, −0.34 ± 1.41 mmHg and 0.21 ± 0.64 breath per minute (bpm) for CO2, EtCO2 and RR. The findings revealed that the developed device is highly reliable, providing valid measurements for CO2, EtCO2, ICO2 and RR, and can be used in clinical settings for cardiorespiratory assessment. This research also demonstrates that EtCO2 and RR (r, −0.696) are negatively correlated while EtCO2 and activity (r, 0.846) are positively correlated. Thus, simultaneous measurement of these features may possibly assist physicians in understanding the subject's cardiopulmonary status. In future, the proposed device will be tested with asthmatic patients for use as an early screening tool outside a hospital setting.
Qizhong Liang et al 2023 J. Breath Res. 17 036001
Rapid testing is essential to fighting pandemics such as coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Exhaled human breath contains multiple volatile molecules providing powerful potential for non-invasive diagnosis of diverse medical conditions. We investigated breath detection of SARS-CoV-2 infection using cavity-enhanced direct frequency comb spectroscopy (CE-DFCS), a state-of-the-art laser spectroscopic technique capable of a real-time massive collection of broadband molecular absorption features at ro-vibrational quantum state resolution and at parts-per-trillion volume detection sensitivity. Using a total of 170 individual breath samples (83 positive and 87 negative with SARS-CoV-2 based on reverse transcription polymerase chain reaction tests), we report excellent discrimination capability for SARS-CoV-2 infection with an area under the receiver-operating-characteristics curve of 0.849(4). Our results support the development of CE-DFCS as an alternative, rapid, non-invasive test for COVID-19 and highlight its remarkable potential for optical diagnoses of diverse biological conditions and disease states.
William R Bishai and Graham S Timmins 2019 J. Breath Res. 13 032002
Roles for urease in virulence are accepted for Helicobacter pylori and urinary tract pathogens. However, urease is widely expressed by bacterial and fungal lung pathogens causing emerging and opportunistic lung infections, organisms causing acute exacerbations of chronic bronchitis, mycobacterial lung diseases such as tuberculosis (TB), and ventilator associated pneumonia and health care associated pneumonia. Detection of urease provides a method for rapid in vivo detection of these lung pathogens by inhaled 13C- breath test, and this review discusses the range of lung pathogens that might be amenable to rapid diagnosis.
Hsuan Chou et al 2024 J. Breath Res. 18 026008
Exhaustive exercise can induce unique physiological responses in the lungs and other parts of the human body. The volatile organic compounds (VOCs) in exhaled breath are ideal for studying the effects of exhaustive exercise on the lungs due to the proximity of the breath matrix to the respiratory tract. As breath VOCs can originate from the bloodstream, changes in abundance should also indicate broader physiological effects of exhaustive exercise on the body. Currently, there is limited published data on the effects of exhaustive exercise on breath VOCs. Breath has great potential for biomarker analysis as it can be collected non-invasively, and capture real-time metabolic changes to better understand the effects of exhaustive exercise. In this study, we collected breath samples from a small group of elite runners participating in the 2019 Ultra-Trail du Mont Blanc ultra-marathon. The final analysis included matched paired samples collected before and after the race from 24 subjects. All 48 samples were analyzed using the Breath Biopsy Platform with GC-Orbitrap™ via thermal desorption gas chromatography-mass spectrometry. The Wilcoxon signed-rank test was used to determine whether VOC abundances differed between pre- and post-race breath samples (adjusted P-value < .05). We identified a total of 793 VOCs in the breath samples of elite runners. Of these, 63 showed significant differences between pre- and post-race samples after correction for multiple testing (12 decreased, 51 increased). The specific VOCs identified suggest the involvement of fatty acid oxidation, inflammation, and possible altered gut microbiome activity in response to exhaustive exercise. This study demonstrates significant changes in VOC abundance resulting from exhaustive exercise. Further investigation of VOC changes along with other physiological measurements can help improve our understanding of the effect of exhaustive exercise on the body and subsequent differences in VOCs in exhaled breath.
P Mochalski et al 2023 J. Breath Res. 17 037101
We summarize the history and review the literature on isoprene in exhaled breath and discuss the current evidence and models that describe its endogenous origin and consequence for understanding isoprene levels and their variations in exhaled breath.
Ruth P Cusack et al 2024 J. Breath Res. 18 026009
Detection of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) relies on real-time-reverse-transcriptase polymerase chain reaction (RT-PCR) on nasopharyngeal swabs. The false-negative rate of RT-PCR can be high when viral burden and infection is localized distally in the lower airways and lung parenchyma. An alternate safe, simple and accessible method for sampling the lower airways is needed to aid in the early and rapid diagnosis of COVID-19 pneumonia. In a prospective unblinded observational study, patients admitted with a positive RT-PCR and symptoms of SARS-CoV-2 infection were enrolled from three hospitals in Ontario, Canada. Healthy individuals or hospitalized patients with negative RT-PCR and without respiratory symptoms were enrolled into the control group. Breath samples were collected and analyzed by laser absorption spectroscopy (LAS) for volatile organic compounds (VOCs) and classified by machine learning (ML) approaches to identify unique LAS-spectra patterns (breathprints) for SARS-CoV-2. Of the 135 patients enrolled, 115 patients provided analyzable breath samples. Using LAS-breathprints to train ML classifier models resulted in an accuracy of 72.2%–81.7% in differentiating between SARS-CoV2 positive and negative groups. The performance was consistent across subgroups of different age, sex, body mass index, SARS-CoV-2 variants, time of disease onset and oxygen requirement. The overall performance was higher than compared to VOC-trained classifier model, which had an accuracy of 63%–74.7%. This study demonstrates that a ML-based breathprint model using LAS analysis of exhaled breath may be a valuable non-invasive method for studying the lower airways and detecting SARS-CoV-2 and other respiratory pathogens. The technology and the ML approach can be easily deployed in any setting with minimal training. This will greatly improve access and scalability to meet surge capacity; allow early and rapid detection to inform therapy; and offers great versatility in developing new classifier models quickly for future outbreaks.
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Barbora Czippelová et al 2024 J. Breath Res. 18 036004
The analysis of volatile organic compounds (VOCs) in exhaled air has attracted the interest of the scientific community because it provides the possibility of monitoring physiological and metabolic processes and non-invasive diagnostics of various diseases. However, this method remains underused in clinical practice as well as in research because of the lack of standardized procedures for the collection, storage and transport of breath samples, which would guarantee good reproducibility and comparability of results. The method of sampling, as well as the storage time of the breath samples in the polymer bags used for sample storage and transport, affect the composition and concentration of VOCs present in the breath samples. The aim of our study was to compare breath samples obtained using two methods with fully disposable equipment: a Haldane sampling tube intended for direct breath collection and breath samples exhaled into a transparent Tedlar bag. The second task was to monitor the stability of selected compounds of real breath samples stored in a Tedlar bag for 6 h. Gas chromatography coupled with ion mobility spectrometry (GC-IMS) implemented in the BreathSpec® device was used to analyse exhaled breath. Our results showed a significant difference in the signal intensity of some volatiles when taking a breath sample with a Haldane tube and a Tedlar bag. Due to its endogenous origin, acetone levels were significantly higher when the Haldane tube sampler was used while elevated levels of 2-propanol and unidentified VOC (designated as VOC 3) in the Tedlar bag samples likely originated from contamination of the Tedlar bags. The VOC stability study revealed compound-specific signal intensity changes of the selected VOCs with storage time in the Tedlar bags, with some volatiles showing increasing signal intensity during storage in Tedlar bags. This limits the use of Tedlar bags only for very limited time and carefully selected purpose. Our results highlight the importance of careful design and implementation of experiments and clinical protocols to obtain relevant and reliable results.
Jonas Herth et al 2024 J. Breath Res. 18 036003
Exhaled breath analysis has emerged as a non-invasive and promising method for early detection of lung cancer, offering a novel approach for diagnosis through the identification of specific biomarkers present in a patient's breath. For this longitudinal study, 29 treatment-naive patients with lung cancer were evaluated before and after surgery. Secondary electrospray ionization high-resolution mass spectrometry was used for exhaled breath analysis. Volatile organic compounds with absolute log2 fold change ⩾1 and q-values ⩾ 0.71 were selected as potentially relevant. Exhaled breath analysis resulted in a total of 3482 features. 515 features showed a substantial difference before and after surgery. The small sample size generated a false positive rate of 0.71, therefore, around 154 of these 515 features were expected to be true changes. Biological identification of the features with the highest consistency (m/z −242.18428 and m/z −117.0539) revealed to potentially be 3-Oxotetradecanoic acid and Indole, respectively. Principal component analysis revealed a primary cluster of patients with a recurrent lung cancer, which remained undetected in the initial diagnostic and surgical procedures. The change of exhaled breath patterns after surgery in lung cancer emphasizes the potential for lung cancer screening and detection.
Ophir Bar-On et al 2024 J. Breath Res. 18 036002
During the COVID-19 pandemic wearing face masks was mandatory. Nowadays, face masks are still encouraged indoors, especially in hospitals. People climbing stairs with masks describe unpredictable dyspnea. In this study, healthy adults climbed 5 floors with and without a mask. Various cardio-respiratory parameters were measured, including O2−saturation (O2−Sat) and end-tidal CO2 (EtCO2), at baseline and on the top floor. Subjective indexes, such as Borg's scale, were evaluated. Thirty-two volunteers (16 males), median age 39 years (IQR 32.5–43), median BMI = 23.6 (IQR 21.5–25.1), with good fitness levels, participated. Comparing baseline to end-activity, median (IQR): O2−Sat change was −1.0% (−2–0) without mask, versus −3.0% (−4–0) with mask, p = 0.003; EtCO2 + 7.0 (+3.3–+9) without mask, versus +8.0 (+6–+12) with mask, p = 0.0001. Hypercarbia was seen in 5 (15.6%) participants without mask, median = 48 mmHg (IQR 47.5–51), and in 11 (34%) participants with mask, median = 50 mmHg (IQR 47–54), p < 0.001. Desaturation (O2−Sat < 95%) was seen in 5 (15.6%) participants without mask, median = 94% (IQR 93%–94%), and in 10 (31%) participants with mask, median = 91.5% (IQR 90%–93%), p = 0.06. Regression analysis demonstrated that only male sex was significantly associated with abnormal EtCO2 (OR = 26.4, 95% CI = 1.9–366.4, p = 0.005). Ascent duration increased from median (IQR) of 94 s (86–100) without mask to 98 s (89–107) with mask, p < 0.001. Borg's scale of perceived exertion (range 0–10) increased from median (IQR) of 3.0 (2.5–3.87) without mask to 4.0 (3.0–4.37) with mask, p < 0.001. To conclude, during routine daily activities, such as stair-climbing, face masks cause dyspnea, and have measurable influences on ventilation, including true desaturation and hypercapnia, especially in males.
P Mochalski et al 2024 J. Breath Res. 18 032001
In the breath research community's search for volatile organic compounds that can act as non-invasive biomarkers for various diseases, hundreds of endogenous volatiles have been discovered. Whilst these systemic chemicals result from normal and abnormal metabolic activities or pathological disorders, to date very few are of any use for the development of clinical breath tests that could be used for disease diagnosis or to monitor therapeutic treatments. The reasons for this lack of application are manifold and complex, and these complications either limit or ultimately inhibit the analytical application of endogenous volatiles for use in the medical sciences. One such complication is a lack of knowledge on the biological origins of the endogenous volatiles. A major exception to this is isoprene. Since 1984, i.e. for 40 years, it has been generally accepted that the pathway to the production of human isoprene, and hence the origin of isoprene in exhaled breath, is through cholesterol biosynthesis via the mevalonate (MVA) pathway within the liver. However, various studies between 2001 and 2012 provide compelling evidence that human isoprene is produced in skeletal muscle tissue. A recent multi-omic investigation of genes and metabolites has revealed that this proposal is correct by showing that human isoprene predominantly results from muscular lipolytic cholesterol metabolism. Despite the overwhelming proof for a muscular pathway to isoprene production in the human body, breath research papers still reference the hepatic MVA pathway. The major aim of this perspective is to review the evidence that leads to a correct interpretation for the origins of human isoprene, so that the major pathway to human isoprene production is understood and appropriately disseminated. This is important, because an accurate attribution to the endogenous origins of isoprene is needed if exhaled isoprene levels are to be correctly interpreted and for assessing isoprene as a clinical biomarker.
Hsuan Chou et al 2024 J. Breath Res. 18 030401
The annual Breath Biopsy Conference hosted by Owlstone Medical gathers together the leading experts, early career researchers, and physicians working with breath as a biomarker platform for clinical purposes. The current topics in breath research are discussed and presented, and an overarching topical theme is identified and discussed as part of an expert panel to close the conference. The profiling of normal breath composition and the establishment of standards for analyzing breath compared to background signal were two important topics that were major focuses of this conference, as well as important innovative progress that has been made since last year, including the development of a non-invasive breath test for lung cancer and liver disease. This meeting report offers an overview of the key take-home messages from the various presentations, posters, and discussions from the conference.
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Manoj Khokhar 2024 J. Breath Res. 18 024001
Breath biomarkers are substances found in exhaled breath that can be used for non-invasive diagnosis and monitoring of medical conditions, including kidney disease. Detection techniques include mass spectrometry (MS), gas chromatography (GC), and electrochemical sensors. Biosensors, such as GC-MS or electronic nose (e-nose) devices, can be used to detect volatile organic compounds (VOCs) in exhaled breath associated with metabolic changes in the body, including the kidneys. E-nose devices could provide an early indication of potential kidney problems through the detection of VOCs associated with kidney dysfunction. This review discusses the sources of breath biomarkers for monitoring renal disease during dialysis and different biosensor approaches for detecting exhaled breath biomarkers. The future of using various types of biosensor-based real-time breathing diagnosis for renal failure is also discussed.
Glívia Maria Barros Delmondes et al 2024 J. Breath Res. 18 014001
Pulmonary function is usually assessed by measuring Vital Capacity (VC) using equipment such as a spirometer or ventilometer, but these are not always available to the population, as they are relatively expensive tests, difficult to transport and require trained professionals. However, the single breath counting technique (SBCT) appears as a possible alternative to respiratory function tests, to help in the pathophysiological understanding of lung diseases. The objective is to verify the applicability of the SBCT as a parameter for evaluating VC. This is a systematic review registered in the International Prospective Register of Systematic Reviews (CRD42023383706) and used for PubMed®, Scientific Electronic Library Online, LILACS, EMBASE, and Web of Science databases of articles published until January 2023. Methodological quality regarding the risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 and National Institutes of Health tools. Eleven of a total of 574 studies were included, of these, nine showed a correlation between VC and SBCT (weak in healthy, moderate in neuromuscular and strong in hospitalized patients). One study of hospitalized patients accurately identified a count value of 21 for a VC of 20 ml kg−1 (Sensitivity = 94% and Specificity = 77%), and another estimated a count lower than 41 for a VC below 80% of predicted in patients with neuromuscular dystrophy (Sensitivity = 89% and Specificity = 62%), and another showed good intra and inter-examiner reproducibility in young, adult, and elderly populations. A meta-analysis of three studies showed a moderate correlation in subjects with neuromuscular diseases (r = 0.62, 95% CI = 0.52–0.71, p < 0.01). A high risk of bias was identified regarding the justification of the sample size and blinding of the evaluators. SBCT has been presented as an alternative to assess VC in the absence of specific equipment. There is a clear relationship between SBCT and VC, especially in neuromuscular and hospitalized individuals. New validation studies conducted with greater control of potential bias risks are necessary.
Veronika Ruzsányi and Miklós Péter Kalapos 2023 J. Breath Res. 17 044001
Owing to its connection to cancer metabolism, lactate is a compound that has been a focus of interest in field of cancer biochemistry for more than a century. Exhaled breath volatile organic compounds (VOCs) and condensate analyses can identify and monitor volatile and non-VOCs, respectively, present in exhaled breath to gain information about the health state of an individual. This work aims to take into account the possible use of breath lactate measurements in tumor diagnosis and treatment control, to discuss technical barriers to measurement, and to evaluate directions for the future improvement of this technique. The use of exhaled breath condensate (EBC) lactic acid levels in disorders other than cancer is also discussed in brief. Whilst the use of EBC for the detection of lactate in exhaled breath is a promising tool that could be used to monitor and screen for cancer, the reliability and sensitivity of detection are uncertain, and hence its value in clinical practice is still limited. Currently, lactate present in plasma and EBC can only be used as a biomarker for advanced cancer, and therefore it presently has limited differential diagnostic importance and is rather of prognostic value.
Rohit Vadala et al 2023 J. Breath Res. 17 024002
Lung cancer is one of the common malignancies with high mortality rate and a poor prognosis. Most lung cancer cases are diagnosed at an advanced stage either due to limited resources of infrastructure, trained human resources, or delay in clinical suspicion. Low-dose computed tomography has emerged as a screening tool for lung cancer detection but this may not be a feasible option for most developing countries. Electronic nose is a unique non-invasive device that has been developed for lung cancer diagnosis and monitoring response by exhaled breath analysis of volatile organic compounds. The breath-print have been shown to differ not only among lung cancer and other respiratory diseases, but also between various types of lung cancer. Hence, we postulate that the breath-print analysis by electronic nose could be a potential biomarker for the early detection of lung cancer along with monitoring treatment response in a resource-limited setting. In this review, we have consolidated the current published literature suggesting the use of an electronic nose in the diagnosis and monitoring treatment response of lung cancer.
Haripriya P et al 2023 J. Breath Res. 17 024001
Early disease detection is often correlated with a reduction in mortality rate and improved prognosis. Currently, techniques like biopsy and imaging that are used to screen chronic diseases are invasive, costly or inaccessible to a large population. Thus, a non-invasive disease screening technology is the need of the hour. Existing non-invasive methods like gas chromatography-mass spectrometry, selected-ion flow-tube mass spectrometry, and proton transfer reaction-mass-spectrometry are expensive. These techniques necessitate experienced operators, making them unsuitable for a large population. Various non-invasive sources are available for disease detection, of which exhaled breath is preferred as it contains different volatile organic compounds (VOCs) that reflect the biochemical reactions in the human body. Disease screening by exhaled breath VOC analysis can revolutionize the healthcare industry. This review focuses on exhaled breath VOC biomarkers for screening various diseases with a particular emphasis on liver diseases and head and neck cancer as examples of diseases related to metabolic disorders and diseases unrelated to metabolic disorders, respectively. Single sensor and sensor array-based (Electronic Nose) approaches for exhaled breath VOC detection are briefly described, along with the machine learning techniques used for pattern recognition.
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Odabaş et al
Despite the widespread use of dental restorative materials, little information exists in the literature regarding their potential impact on bad breath. This in vitro study aims to fill this gap by investigating the influence of different restorative materials on the release of hydrogen sulfide (H2S). Thirteen diverse dental restorative materials, including composites, flowable composites, glass ionomer restorative materials, high-copper amalgam, and CAD-CAM blocks, were examined. Cellulose Sponge models were used as negative and positive control. All samples were prepared with a diameter of 5 mm and a height of 2 mm. Except for the negative control group, all samples were embedded into Allium cepa L., and the emitted H2S was measured using the Wintact W8802 hydrogen sulfide monitor.
Surface roughness's effect on emission was explored by roughening the surfaces of CAD-CAM material samples, and gas emission was measured again. The data were statistically analyzed using the Kruskal-Wallis test and DSCF pairwise comparison tests. Fiber-reinforced flowable composite (EverX Flow), amalgam (Nova 70-caps), and certain composite materials (IPS Empress Direct, Tetric Evoceram, Admira Fusion X-tra) released higher H2S concentrations compared to the negative control. The H2S release period lasted longer in the same materials mentioned above, along with G-aenial Universal Injectable. Indirectly used materials, such as GC Cerasmart, Vita Enamic, and Vita YZ HT, demonstrated significantly lower emissions compared to other direct restoratives. Importantly, the surface roughness of indirect materials did not significantly affect peak H2S concentrations or release times. The study reveals variations in H2S release among restorative materials, suggesting potential advantages of indirect restorative materials in reducing H2S-induced halitosis.
This comprehensive understanding of the relationship between restorative materials and halitosis can empower both dental professionals and patients to make well-informed treatment choices. Notably, there is evidence supporting the enhanced performance of indirect restorative materials for individuals affected by halitosis.
Högman
Standardisation is the road to improvement! If we all measure exhaled nitric oxide (NO) the same way, we will be successful in having data to make reference questions. Many research groups have published their reference equation, but most differ considerably. About 25 years ago, using the flow of 50 mL s-1 was recommended and not using a nose clip. When collecting data worldwide, we still see publications that do not indicate what flow was used and that nose clip was utilised. Three things are needed: the analysing method, a flow recording and a filled-in nitric oxide questionnaire. The analysing method is because the techniques have different sensitivity, response times and calibration. The flow of 50 mL s-1 is on the steep part of the NO output curve; therefore, we need to record the flow to analyse repeated measurements or compare results. The NO questionnaire controls individual factors that may influence the NO measurements, i.e., food intake, smoking and upper airway infection. An important tool in following old and new disease treatments, at home or in health care, is exhaled biomarkers. If we follow the standardisation we have agreed upon, we will be able to have data to say what a high or a low exhaled NO value is.
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Barbora Czippelová et al 2024 J. Breath Res. 18 036004
The analysis of volatile organic compounds (VOCs) in exhaled air has attracted the interest of the scientific community because it provides the possibility of monitoring physiological and metabolic processes and non-invasive diagnostics of various diseases. However, this method remains underused in clinical practice as well as in research because of the lack of standardized procedures for the collection, storage and transport of breath samples, which would guarantee good reproducibility and comparability of results. The method of sampling, as well as the storage time of the breath samples in the polymer bags used for sample storage and transport, affect the composition and concentration of VOCs present in the breath samples. The aim of our study was to compare breath samples obtained using two methods with fully disposable equipment: a Haldane sampling tube intended for direct breath collection and breath samples exhaled into a transparent Tedlar bag. The second task was to monitor the stability of selected compounds of real breath samples stored in a Tedlar bag for 6 h. Gas chromatography coupled with ion mobility spectrometry (GC-IMS) implemented in the BreathSpec® device was used to analyse exhaled breath. Our results showed a significant difference in the signal intensity of some volatiles when taking a breath sample with a Haldane tube and a Tedlar bag. Due to its endogenous origin, acetone levels were significantly higher when the Haldane tube sampler was used while elevated levels of 2-propanol and unidentified VOC (designated as VOC 3) in the Tedlar bag samples likely originated from contamination of the Tedlar bags. The VOC stability study revealed compound-specific signal intensity changes of the selected VOCs with storage time in the Tedlar bags, with some volatiles showing increasing signal intensity during storage in Tedlar bags. This limits the use of Tedlar bags only for very limited time and carefully selected purpose. Our results highlight the importance of careful design and implementation of experiments and clinical protocols to obtain relevant and reliable results.
Jonas Herth et al 2024 J. Breath Res. 18 036003
Exhaled breath analysis has emerged as a non-invasive and promising method for early detection of lung cancer, offering a novel approach for diagnosis through the identification of specific biomarkers present in a patient's breath. For this longitudinal study, 29 treatment-naive patients with lung cancer were evaluated before and after surgery. Secondary electrospray ionization high-resolution mass spectrometry was used for exhaled breath analysis. Volatile organic compounds with absolute log2 fold change ⩾1 and q-values ⩾ 0.71 were selected as potentially relevant. Exhaled breath analysis resulted in a total of 3482 features. 515 features showed a substantial difference before and after surgery. The small sample size generated a false positive rate of 0.71, therefore, around 154 of these 515 features were expected to be true changes. Biological identification of the features with the highest consistency (m/z −242.18428 and m/z −117.0539) revealed to potentially be 3-Oxotetradecanoic acid and Indole, respectively. Principal component analysis revealed a primary cluster of patients with a recurrent lung cancer, which remained undetected in the initial diagnostic and surgical procedures. The change of exhaled breath patterns after surgery in lung cancer emphasizes the potential for lung cancer screening and detection.
Marieann Högman 2024 J. Breath Res.
Standardisation is the road to improvement! If we all measure exhaled nitric oxide (NO) the same way, we will be successful in having data to make reference questions. Many research groups have published their reference equation, but most differ considerably. About 25 years ago, using the flow of 50 mL s-1 was recommended and not using a nose clip. When collecting data worldwide, we still see publications that do not indicate what flow was used and that nose clip was utilised. Three things are needed: the analysing method, a flow recording and a filled-in nitric oxide questionnaire. The analysing method is because the techniques have different sensitivity, response times and calibration. The flow of 50 mL s-1 is on the steep part of the NO output curve; therefore, we need to record the flow to analyse repeated measurements or compare results. The NO questionnaire controls individual factors that may influence the NO measurements, i.e., food intake, smoking and upper airway infection. An important tool in following old and new disease treatments, at home or in health care, is exhaled biomarkers. If we follow the standardisation we have agreed upon, we will be able to have data to say what a high or a low exhaled NO value is.
P Mochalski et al 2024 J. Breath Res. 18 032001
In the breath research community's search for volatile organic compounds that can act as non-invasive biomarkers for various diseases, hundreds of endogenous volatiles have been discovered. Whilst these systemic chemicals result from normal and abnormal metabolic activities or pathological disorders, to date very few are of any use for the development of clinical breath tests that could be used for disease diagnosis or to monitor therapeutic treatments. The reasons for this lack of application are manifold and complex, and these complications either limit or ultimately inhibit the analytical application of endogenous volatiles for use in the medical sciences. One such complication is a lack of knowledge on the biological origins of the endogenous volatiles. A major exception to this is isoprene. Since 1984, i.e. for 40 years, it has been generally accepted that the pathway to the production of human isoprene, and hence the origin of isoprene in exhaled breath, is through cholesterol biosynthesis via the mevalonate (MVA) pathway within the liver. However, various studies between 2001 and 2012 provide compelling evidence that human isoprene is produced in skeletal muscle tissue. A recent multi-omic investigation of genes and metabolites has revealed that this proposal is correct by showing that human isoprene predominantly results from muscular lipolytic cholesterol metabolism. Despite the overwhelming proof for a muscular pathway to isoprene production in the human body, breath research papers still reference the hepatic MVA pathway. The major aim of this perspective is to review the evidence that leads to a correct interpretation for the origins of human isoprene, so that the major pathway to human isoprene production is understood and appropriately disseminated. This is important, because an accurate attribution to the endogenous origins of isoprene is needed if exhaled isoprene levels are to be correctly interpreted and for assessing isoprene as a clinical biomarker.
Julia Eichinger et al 2024 J. Breath Res. 18 036001
We explored appropriate technical setups for the detection of volatile organic compounds (VOCs) from exhaled cow breath by comparing six different polymer-based solid-phase extraction (SPE) cartridges currently on the market for gas chromatography/mass spectrometry (GC-MS) screening. Exhaled breath was sampled at a single timepoint from five lactating dairy cows using six different SPE cartridges (Bond Elut ENV (ENV); Chromabond HRX (HRX); Chromabond HRP (HRP); Chromabond HLB (HLB); Chromabond HR-XCW (XCW) and Chromabond HR-XAW (XAW)). The trapped VOCs were analyzed by dynamic headspace vacuum in-tube extraction GC-MS (DHS-V-ITEX-GC-MS). Depending on the SPE cartridge, we detected 1174–1312 VOCs per cartridge. Most VOCs were alkenes, alkanes, esters, ketones, alcohols, aldehydes, amines, nitriles, ethers, amides, carboxylic acids, alkynes, azoles, terpenes, pyridines, or sulfur-containing compounds. The six SPE cartridges differed in their specificity for the chemical compounds, with the XAW cartridge showing the best specificity for ketones. The greatest differences between the tested SPE cartridges appeared in the detection of specific VOCs. In total, 176 different VOCs were detected with a match factor >80%. The greatest number of specific VOCs was captured by XAW (149), followed by ENV (118), HLB (117), HRP (115), HRX (114), and XCW (114). We conclude that the tested SPE cartridges are suitable for VOC sampling from exhaled cow breath, but the SPE cartridge choice enormously affects the detected chemical groups and the number of detected VOCs. Therefore, an appropriate SPE adsorbent cartridge should be selected according to our proposed inclusion criteria. For targeted metabolomics approaches, the SPE cartridge choice depends on the VOCs or chemical compound groups of interest based on our provided VOC list. For untargeted approaches without information on the animals' metabolic condition, we suggest using multi-sorbent SPE cartridges or multiple cartridges per animal.
Ruth P Cusack et al 2024 J. Breath Res. 18 026009
Detection of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) relies on real-time-reverse-transcriptase polymerase chain reaction (RT-PCR) on nasopharyngeal swabs. The false-negative rate of RT-PCR can be high when viral burden and infection is localized distally in the lower airways and lung parenchyma. An alternate safe, simple and accessible method for sampling the lower airways is needed to aid in the early and rapid diagnosis of COVID-19 pneumonia. In a prospective unblinded observational study, patients admitted with a positive RT-PCR and symptoms of SARS-CoV-2 infection were enrolled from three hospitals in Ontario, Canada. Healthy individuals or hospitalized patients with negative RT-PCR and without respiratory symptoms were enrolled into the control group. Breath samples were collected and analyzed by laser absorption spectroscopy (LAS) for volatile organic compounds (VOCs) and classified by machine learning (ML) approaches to identify unique LAS-spectra patterns (breathprints) for SARS-CoV-2. Of the 135 patients enrolled, 115 patients provided analyzable breath samples. Using LAS-breathprints to train ML classifier models resulted in an accuracy of 72.2%–81.7% in differentiating between SARS-CoV2 positive and negative groups. The performance was consistent across subgroups of different age, sex, body mass index, SARS-CoV-2 variants, time of disease onset and oxygen requirement. The overall performance was higher than compared to VOC-trained classifier model, which had an accuracy of 63%–74.7%. This study demonstrates that a ML-based breathprint model using LAS analysis of exhaled breath may be a valuable non-invasive method for studying the lower airways and detecting SARS-CoV-2 and other respiratory pathogens. The technology and the ML approach can be easily deployed in any setting with minimal training. This will greatly improve access and scalability to meet surge capacity; allow early and rapid detection to inform therapy; and offers great versatility in developing new classifier models quickly for future outbreaks.
Hsuan Chou et al 2024 J. Breath Res. 18 026008
Exhaustive exercise can induce unique physiological responses in the lungs and other parts of the human body. The volatile organic compounds (VOCs) in exhaled breath are ideal for studying the effects of exhaustive exercise on the lungs due to the proximity of the breath matrix to the respiratory tract. As breath VOCs can originate from the bloodstream, changes in abundance should also indicate broader physiological effects of exhaustive exercise on the body. Currently, there is limited published data on the effects of exhaustive exercise on breath VOCs. Breath has great potential for biomarker analysis as it can be collected non-invasively, and capture real-time metabolic changes to better understand the effects of exhaustive exercise. In this study, we collected breath samples from a small group of elite runners participating in the 2019 Ultra-Trail du Mont Blanc ultra-marathon. The final analysis included matched paired samples collected before and after the race from 24 subjects. All 48 samples were analyzed using the Breath Biopsy Platform with GC-Orbitrap™ via thermal desorption gas chromatography-mass spectrometry. The Wilcoxon signed-rank test was used to determine whether VOC abundances differed between pre- and post-race breath samples (adjusted P-value < .05). We identified a total of 793 VOCs in the breath samples of elite runners. Of these, 63 showed significant differences between pre- and post-race samples after correction for multiple testing (12 decreased, 51 increased). The specific VOCs identified suggest the involvement of fatty acid oxidation, inflammation, and possible altered gut microbiome activity in response to exhaustive exercise. This study demonstrates significant changes in VOC abundance resulting from exhaustive exercise. Further investigation of VOC changes along with other physiological measurements can help improve our understanding of the effect of exhaustive exercise on the body and subsequent differences in VOCs in exhaled breath.
Robert van Vorstenbosch et al 2024 J. Breath Res. 18 026007
Disease detection and monitoring using volatile organic compounds (VOCs) is becoming increasingly popular. For a variety of (gastrointestinal) diseases the microbiome should be considered. As its output is to large extent volatile, faecal volatilomics carries great potential. One technical limitation is that current faecal headspace analysis requires specialized instrumentation which is costly and typically does not work in harmony with thermal desorption units often utilized in e.g. exhaled breath studies. This lack of harmonization hinders uptake of such analyses by the Volatilomics community. Therefore, this study optimized and compared two recently harmonized faecal headspace sampling platforms: High-capacity Sorptive extraction (HiSorb) probes and the Microchamber thermal extractor (Microchamber). Statistical design of experiment was applied to find optimal sampling conditions by maximizing reproducibility, the number of VOCs detected, and between subject variation. To foster general applicability those factors were defined using semi-targeted as well as untargeted metabolic profiles. HiSorb probes were found to result in a faster sampling procedure, higher number of detected VOCs, and higher stability. The headspace collection using the Microchamber resulted in a lower number of detected VOCs, longer sampling times and decreased stability despite a smaller number of interfering VOCs and no background signals. Based on the observed profiles, recommendations are provided on pre-processing and study design when using either one of both platforms. Both can be used to perform faecal headspace collection, but altogether HiSorb is recommended.
Xiaoxiao Li et al 2024 J. Breath Res. 18 026004
The correlation between propofol concentration in exhaled breath (CE) and plasma (CP) has been well-established, but its applicability for estimating the concentration in brain tissues (CB) remains unknown. Given the impracticality of directly sampling human brain tissues, rats are commonly used as a pharmacokinetic model due to their similar drug-metabolizing processes to humans. In this study, we measured CE, CP, and CB in mechanically ventilated rats injected with propofol. Exhaled breath samples from the rats were collected every 20 s and analyzed using our team's developed vacuum ultraviolet time-of-flight mass spectrometry. Additionally, femoral artery blood samples and brain tissue samples at different time points were collected and measured using high-performance liquid chromatography mass spectrometry. The results demonstrated that propofol concentration in exhaled breath exhibited stronger correlations with that in brain tissues compared to plasma levels, suggesting its potential suitability for reflecting anesthetic action sites' concentrations and anesthesia titration. Our study provides valuable animal data supporting future clinical applications.
Zachary Joseph Sasiene et al 2024 J. Breath Res. 18 026003
The direct analysis of molecules contained within human breath has had significant implications for clinical and diagnostic applications in recent decades. However, attempts to compare one study to another or to reproduce previous work are hampered by: variability between sampling methodologies, human phenotypic variability, complex interactions between compounds within breath, and confounding signals from comorbidities. Towards this end, we have endeavored to create an averaged healthy human 'profile' against which follow-on studies might be compared. Through the use of direct secondary electrospray ionization combined with a high-resolution mass spectrometry and in-house bioinformatics pipeline, we seek to curate an average healthy human profile for breath and use this model to distinguish differences inter- and intra-day for human volunteers. Breath samples were significantly different in PERMANOVA analysis and ANOSIM analysis based on Time of Day, Participant ID, Date of Sample, Sex of Participant, and Age of Participant (p < 0.001). Optimal binning analysis identify strong associations between specific features and variables. These include 227 breath features identified as unique identifiers for 28 of the 31 participants. Four signals were identified to be strongly associated with female participants and one with male participants. A total of 37 signals were identified to be strongly associated with the time-of-day samples were taken. Threshold indicator taxa analysis indicated a shift in significant breath features across the age gradient of participants with peak disruption of breath metabolites occurring at around age 32. Forty-eight features were identified after filtering from which a healthy human breath profile for all participants was created.