Detection ofClostridioides difficileinfection by assessment of exhaled breath volatile organic compounds.

Clostridioides difficileinfection (CDI) is the leading cause of hospital-acquired infective diarrhea. Current methods for diagnosing CDI have limitations; enzyme immunoassays for toxin have low sensitivity andClostridioides difficilepolymerase chain reaction cannot differentiate infection from colonization. An ideal diagnostic test that incorporates microbial factors, host factors, and host-microbe interaction might characterize true infection. Assessing volatile organic compounds (VOCs) in exhaled breath may be a useful test for identifying CDI. To identify a wide selection of VOCs in exhaled breath, we used thermal desorption-gas chromatography-mass spectrometry to study breath samples from 17 patients with CDI. Age- and sex-matched patients with diarrhea and negativeC.difficiletesting (no CDI) were used as controls. Of the 65 VOCs tested, 9 were used to build a quadratic discriminant model that showed a final cross-validated accuracy of 74%, a sensitivity of 71%, a specificity of 76%, and a receiver operating characteristic area under the curve of 0.72. If these findings are proven by larger studies, breath VOC analysis may be a helpful adjunctive diagnostic test for CDI.

Exhaled Breath Analysis Using Selected Ion Flow Tube Mass Spectrometry and Disease Severity in Heart Failure.

Exhaled breath volatile organic compounds (VOCs) are elevated in heart failure (HF). The ability of VOCs to predict long term cardiovascular mortality and morbidity has not been independently verified. In 55 patients admitted with acute decompensated heart failure (ADHF), we measured exhaled breath acetone and pentane levels upon admission and after 48 h of diuresis. In a separate cohort of 51 cardiac patients undergoing cardiopulmonary exercise testing (CPET), we measured exhaled breath acetone and pentane levels before and at peak exercise. In the ADHF cohort, admission acetone levels correlated with lower left ventricular ejection fraction (LVEF, r = -0.297, p = 0.035). Greater weight loss with diuretic therapy correlated with a greater reduction in both acetone levels (r = -0.398, p = 0.003) and pentane levels (r = -0.309, p = 0.021). In patients with above-median weight loss (≥4.5 kg), patients demonstrated significantly greater percentage reduction in acetone (59% reduction vs. 7% increase, p < 0.001) and pentane (23% reduction vs. 2% reduction, p = 0.008). In the CPET cohort, admission acetone and pentane levels correlated with higher VE/VCO2 (r = 0.39, p = 0.005), (r = 0.035, p = 0.014). However, there were no significant correlations between baseline or peak exercise acetone and pentane levels and peak VO2. In longitudinal follow-up with a median duration of 33 months, patients with elevated exhaled acetone and pentane levels experienced higher composite adverse events of death, ventricular assist device implantation, or orthotopic heart transplantation. In patients admitted with ADHF, higher exhaled breath acetone levels are associated with lower LVEF and poorer outcomes, and greater reductions in exhaled breath acetone and pentane tracked with greater weight loss. Exhaled acetone and pentane may be novel biomarkers in heart failure worthy of future investigation.

Biomarkers for the Evaluation of Pouch Inflammation: A Systematic Review.

Background: Ileal pouch inflammation is a common problem following ileal pouch-anal anastomosis (IPAA). Despite its prevalence, diagnosis remains multimodal and requires endoscopy. The use of biomarkers in the prediction of and/or association with pouchitis has not been well characterized. We performed a systematic review to summarize the available evidence. Method: A search of Ovid, MEDLINE, Cochrane Library, EMBASE, and Web of Science was conducted. Inclusion criteria included studies evaluating biomarkers for the evaluation and prediction of inflammation in patients with IPAA utilizing pouchoscopy as the gold standard. Exclusion criteria included studies on the role of the microbiome or genetic markers. Results: A total of 28 studies, 5 case-control studies, and 23 observational cohort studies were identified. Fecal biomarkers were assessed in 23 studies, of which fecal calprotectin was the most commonly studied with sensitivities ranging from 57% to 92% and specificities from 19% to 92%. Six studies examined serum biomarkers. None of the serum biomarkers demonstrated a high sensitivity or specificity in association with pouch inflammation. Six studies described the longitudinal assessment of biomarkers. Of these studies, only three reported a predictive role of biomarkers in diagnosing endoscopic inflammation. Conclusions: Biomarkers have emerged as a potential option to improve the management of pouchitis given the relative ease of sampling compared to pouchoscopy. Unfortunately, the evaluated biomarkers have not consistently demonstrated accuracy in predicting inflammation. Moreover, these biomarkers have not been reliably shown to be sensitive or specific in association with endoscopic pouch inflammation to merit their widespread use in clinical practice.

The breath print represents a novel biomarker of malnutrition in pulmonary arterial hypertension: A proof of concept study.

BACKGROUND: The breath print is a quantitative measurement of molecules in exhaled breath and represents a new frontier for biomarker identification. It is unknown whether this state-of-the-art, noninvasive method can detect malnutrition. We hypothesize that individuals with malnutrition will present with a distinguishable breath print. METHODS: We conducted a retrospective chart review on patients with previously analyzed breath samples to identify malnutrition. Breath was analyzed by selected-ion flow-tube mass spectrometry. Registered dietitians conducted a retrospective chart review to collect malnutrition diagnoses and nutrition status indicators. Patients were categorized into one of four groups: pulmonary arterial hypertension (PAH), PAH with malnutrition (PAH-Mal), control, and control with malnutrition (Control-Mal), based on the malnutrition diagnosis present in the patient's chart. Principle component analysis was conducted to characterize the breath print. A logistic regression model with forward selection was used to detect the best breath predictor combination of malnutrition. RESULTS: A total of 74 patients met inclusion criteria (PAH: 52; PAH-Mal: 10; control: 10; Control-Mal: 2). Levels of 1-octene (PAH-Mal, 5.1 ± 1.2; PAH, 12.5 ± 11.2; P = 0.005) and ammonia (PAH-Mal, 14.6 ± 15.8; PAH, 56.2 ± 64.2; P = 0.013) were reduced in PAH-Mal compared with PAH. The combination of 1-octene (P = 0.010) and 3-methylhexane (P = 0.045) distinguished malnutrition in PAH (receiver operating characteristic area under the curve: 0.8549). CONCLUSIONS: This proof of concept study provides the first evidence that the breath print is altered in malnutrition. Larger prospective studies are needed to validate these results and establish whether breath analysis may be a useful tool to screen for malnutrition in the clinical setting.

Diagnosis of Clostridioides difficile infection by analysis of volatile organic compounds in breath, plasma, and stool: A cross-sectional proof-of-concept study.

Clostridioides difficile infection (CDI) is an important infectious cause of antibiotic-associated diarrhea, with significant morbidity and mortality. Current diagnostic algorithms are based on identifying toxin by enzyme immunoassay (EIA) and toxin gene by real-time polymerase chain reaction (PCR) in patients with diarrhea. EIA's sensitivity is poor, and PCR, although highly sensitive and specific, cannot differentiate infection from colonization. An ideal test that incorporates microbial factors, host factors, and host-microbe interaction might characterize true infection, and assess prognosis and recurrence. The study of volatile organic compounds (VOCs) has the potential to be an ideal diagnostic test. The presence of VOCs accounts for the characteristic odor of stool in CDI but their presence in breath and plasma has not been studied yet. A cross-sectional proof-of-concept study analyzing VOCs using selected ion flow tube mass spectrometry (SIFT-MS) was done on breath, stool, and plasma of patients with clinical features and positive PCR for CDI (cases) and compared with patients with clinical features but a negative PCR (control). Our results showed that VOC patterns in breath, stool, and plasma, had good accuracy [area under the receiver operating characteristic curve (ROC) 93%, 86%, and 91%, respectively] for identifying patients with CDI.

Volatile organic compounds in bile can distinguish pancreatic cancer from chronic pancreatitis: a prospective observational study.

BACKGROUND: Early and accurate diagnosis of pancreatic cancer is important. Our aim was to identify potential volatile organic compounds (VOCs) in the bile that can help distinguish pancreatic cancer from chronic pancreatitis. METHODS: In this prospective observational study, bile was aspirated from patients undergoing endoscopic retrograde cholangiopancreatography for chronic pancreatitis and pancreatic cancer, and the gaseous headspace was analyzed using mass spectrometry. RESULTS: The study included a discovery cohort of 57 patients (46 pancreatic cancer, 11 chronic pancreatitis) and a validation cohort of 31 patients (19 and 12, respectively). Using logistic regression analysis, the model [0.158 × age + 9.747 × log (ammonia) - 3.994 × log (acetonitrile) + 5.044 × log (trimethylamine) - 30.23] successfully identified patients with pancreatic cancer with a sensitivity of 93.5 % and specificity of 100 % (likelihood ratio 40.9, area under the curve 0.98, 95 % confidence interval 0.95 - 1.00). The diagnostic accuracy of this model was confirmed in the second independent validation cohort. CONCLUSION: The measurement of VOCs in bile helped to accurately distinguish pancreatic cancer from chronic pancreatitis.

Breath Metabolomics Provides an Accurate and Noninvasive Approach for Screening Cirrhosis, Primary, and Secondary Liver Tumors.

Hepatocellular carcinoma (HCC) and secondary liver tumors, such as colorectal cancer liver metastases are significant contributors to the overall burden of cancer-related morality. Current biomarkers, such as alpha-fetoprotein (AFP) for HCC, result in too many false negatives, necessitating noninvasive approaches with improved sensitivity. Volatile organic compounds (VOCs) detected in the breath of patients can provide valuable insight into disease processes and can differentiate patients by disease status. Here, we investigate whether 22 VOCs from the breath of 296 patients can distinguish those with no liver disease (n = 54), cirrhosis (n = 30), HCC (n = 112), pulmonary hypertension (n = 49), or colorectal cancer liver metastases (n = 51). This work extends previous studies by evaluating the ability for VOC signatures to differentiate multiple diseases in a large cohort of patients. Pairwise disease comparisons demonstrated that most of the VOCs tested are present in significantly different relative abundances (false discovery rate P < 0.1), indicating broad impacts on the breath metabolome across diseases. A predictive model developed using random forest machine learning and cross validation classified patients with 85% classification accuracy and 75% balanced accuracy. Importantly, the model detected HCC with 73% sensitivity compared with 53% for AFP in the same cohort. An added value of this approach is that influential VOCs in the predictive model may provide insight into disease etiology. Acetaldehyde and acetone, both of which have roles in tumor promotion, were considered important VOCs for differentiating disease groups in the predictive model and were increased in patients with cirrhosis and HCC compared to patients with no liver disease (false discovery rate P < 0.1). Conclusion: The use of machine learning and breath VOCs shows promise as an approach to develop improved, noninvasive screening tools for chronic liver disease and primary and secondary liver tumors.

Comparison of volatile organic compound profiles in exhaled breath versus plasma headspace in different diseases.

Breath analysis is the study of volatile organic compounds (VOC's) in exhaled breath. This analysis provides information on the body's condition. In this study we investigated the relationship between 22 VOC's detected in exhaled breath and plasma headspace using a selected ion flow tube mass spectrometer (SYFT-MS). We compared pairs of exhaled breath and plasma samples from patients with pulmonary hypertension inflammatory bowel disease (IBD), and IBD patients after J-pouch surgery (pouch group). Half of the measured VOC's from exhaled breath were significantly associated with the VOC's from plasma headspace. Interestingly, six breath VOC's (trimethyl amine (FDR p = 0.02), hydrogen sulfide (FDR p = 7.64 × 10-30), ethanol (FDR p = 1.56 × 10-4), dimethyl sulfide (FDR p = 5.70 × 10-19), benzene (FDR p = 8.40 × 10-27), and acetaldehyde (FDR p = 4.27 × 10-17)) and two plasma headspace VOC's (1-Octene (FDR p = 0.02) and 2-propanol (FDR p = 2.47 × 10-9)) were able to differentiate between the three groups. Breath and plasma headspace share a similar signature with significant association in half of the measured VOCs. The disease discriminatory capacity of breath and plasma headspace appear to be different. Therefore, using the VOC's print from both breath and plasma headspace may better help diagnose patients.

Breath analysis in gastrointestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Volatile organic compounds (VOCs) are generated during pathologic processes, and their assessment can be used to diagnose and monitor a variety of diseases. Given the role of the microbiome in graft-versus-host disease (GVHD), we hypothesized that microorganisms producing volatile metabolites may alter VOCs expelled in breath in patients with gastrointestinal (GI) GVHD. In this pilot study, exhaled breath samples were obtained from 19 patients with grade 2 to 4 acute GI GVHD, 10 patients with no GVHD at day 100, and 10 healthy control subjects; the samples were analyzed by using mass spectrometry. Overall, nine (47%) patients had grade 2 GVHD, eight (42%) patients had grade 3 GVHD, and two (11%) patients had grade 4 GVHD; 26% had upper GI, 21% had lower GI, and 53% had both upper and lower GI manifestations. Stepwise canonical discriminant analysis identified 5 VOCs distinguishing patients with and without GI GVHD: 2-propanol, acetaldehyde, dimethyl sulfide, isoprene, and 1-decene (Wilks' Λ, 0.43; F statistic, 6.08; P = .001). The model correctly classified 89% (17 of 19) and 90% (9 of 10) of patients with and without GI GVHD, respectively. Breath analysis is a feasible and promising noninvasive method to detect acute GI GVHD. Further study of serial breath analysis and the gut microbiome in a larger cohort are ongoing to validate these findings.

Non-enzymatic hydrogen sulfide production from cysteine in blood is catalyzed by iron and vitamin B6.

Hydrogen sulfide (H2S) plays important roles in metabolism and health. Its enzymatic generation from sulfur-containing amino acids (SAAs) is well characterized. However, the existence of non-enzymatic H2S production from SAAs, the chemical mechanism, and its biological implications remain unclear. Here we present non-enzymatic H2S production in vitro and in blood via a reaction specific for the SAA cysteine serving as substrate and requires coordinated catalysis by Vitamin B6, pyridoxal(phosphate), and iron under physiological conditions. An initial cysteine-aldimine is formed by nucleophilic attack of the cysteine amino group to the pyridoxal(phosphate) aldehyde group. Free or heme-bound iron drives the formation of a cysteine-quinonoid, thiol group elimination, and hydrolysis of the desulfurated aldimine back to pyridoxal(phosphate). The reaction ultimately produces pyruvate, NH3, and H2S. This work highlights enzymatic production is inducible and robust in select tissues, whereas iron-catalyzed production contributes underappreciated basal H2S systemically with pathophysiological implications in hemolytic, iron overload, and hemorrhagic disorders.

Molecular breath analysis identifies the breathprint of renal failure.

Many uremic solutes retained in chronic kidney disease are volatile, and can be detected by breath testing. We compared the exhaled breath of subjects with end stage renal disease (ESRD) to healthy volunteers to identify volatile compounds that can serve as a potential breathprint for renal failure. We analyzed the exhaled breath of 86 ESRD subjects and 25 healthy volunteers using selected-ion flow-tube mass spectrometry (SIFT-MS). Using a random forests classification model, we identified three known volatiles (2-propanol, ammonia, acetaldehyde) and two unknown volatiles ([Formula: see text] NO+76) that were highly significant for discriminating individuals with renal failure from individuals without renal failure (C statistic > 0.99). This study provides preliminary support for the use of exhaled breath as a potential noninvasive screening tool in renal failure.

A Distinct Colon-Derived Breath Metabolome is Associated with Inflammatory Bowel Disease, but not its Complications.

OBJECTIVES: The accuracy of available noninvasive biomarkers for diagnosis, stratification, and prediction of inflammatory bowel disease (IBD) courses is limited. We analyzed volatile organic compounds (VOCs) in the breath of IBD patients and controls for diagnosis and differentiation of IBD as well as their link with disease location, activity, and phenotype. METHODS: A prospective study of diagnostic testing was conducted, recruiting Crohn's disease (CD), ulcerative colitis (UC), other inflammatory gastrointestinal diseases (OGDs), and healthy controls (HCs), as well as subjects with ileal pouch anal anastomosis (IPAA). The breath VOC profile was analyzed using selective ion flow tube-mass spectrometry. RESULTS: One hundred and twenty-four subjects (n=24 CD, n=11 UC, n=6 OGD, n=53 HC, n=30 IPAA) were included. The breath metabolome was significantly different in patients with IBD, CD, or UC compared with OGD and HC (7 out of 22 VOCs), but not between CD and UC. No link between the level of VOCs with complications, disease location, and clinical or radiologic disease activity, as well as lab parameters or type of medication was found. Breath VOCs were markedly different in patients with IPAA compared with any other group (17 out of 22 VOCs) and the presence of pouch inflammation did not alter the VOC levels. CONCLUSIONS: A specific breath metabolome is associated with IBD and markedly changes in patients with IPAA. Analysis of a broader spectrum of VOCs can potentially aid in the development of breath prints to diagnose or differentiate inflammatory bowel disorders.

Metabolomics studies identify novel diagnostic and prognostic indicators in patients with alcoholic hepatitis.

AIM: To identify plasma analytes using metabolomics that correlate with the diagnosis and severity of liver disease in patients with alcoholic hepatitis (AH). METHODS: We prospectively recruited patients with cirrhosis from AH (n = 23) and those with cirrhosis with acute decompensation (AD) from etiologies other than alcohol (n = 25). We used mass spectrometry to identify 29 metabolic compounds in plasma samples from fasted subjects. A receiver operating characteristics analysis was performed to assess the utility of biomarkers in distinguishing acute AH from alcoholic cirrhosis. Logistic regression analysis was performed to build a predictive model for AH based on clinical characteristics. A survival analysis was used to construct Kaplan Meier curves evaluating transplant-free survival. RESULTS: A comparison of model for end-stage liver disease (MELD)-adjusted metabolomics levels between cirrhosis patients who had AD or AH showed that patients with AH had significantly higher levels of betaine, and lower creatinine, phenylalanine, homocitrulline, citrulline, tyrosine, octenoyl-carnitine, and symmetric dimethylarginine. When considering combined levels, betaine and citrulline were highly accurate predictors for differentiation between AH and AD (area under receiver operating characteristics curve = 0.84). The plasma levels of carnitine [0.54 (0.18, 0.91); P = 0.005], homocitrulline [0.66 (0.34, 0.99); P < 0.001] and pentanoyl-carnitine [0.53 (0.16, 0.90); P = 0.007] correlated with MELD scores in patients diagnosed with AH. Increased levels of many biomarkers (carnitine P = 0.005, butyrobetaine P = 0.32, homocitrulline P = 0.002, leucine P = 0.027, valine P = 0.024, phenylalanine P = 0.037, tyrosine P = 0.012, acetyl-carnitine P = 0.006, propionyl-carnitine P = 0.03, butyryl-carnitine P = 0.03, trimethyl-lisine P = 0.034, pentanoyl-carnitine P = 0.03, hexanoyl-carnitine P = 0.026) were associated with increased mortality in patients with AH. CONCLUSION: Metabolomics plasma analyte levels might be used to diagnose of AH or help predict patient prognoses.

Novel methods in pulmonary hypertension phenotyping in the age of precision medicine (2015 Grover Conference series).

Among pulmonary vascular diseases, pulmonary hypertension (PH) is the best studied and has been the focus of our work. The current classification of PH is based on a relatively simple combination of patient characteristics and hemodynamics. This leads to inherent limitations, including the inability to customize treatment and the lack of clarity from a more granular identification based on individual patient phenotypes. Accurate phenotyping of PH can be used in the clinic to select therapies and determine prognosis and in research to increase the homogeneity of study cohorts. Rapid advances in the mechanistic understanding of the disease, improved imaging methods, and innovative biomarkers now provide an opportunity to define novel PH phenotypes. We have recently shown that altered metabolism may affect nitric oxide levels and protein glycosylation, the peripheral circulation (which may provide insights into the response to therapy), and exhaled-breath analysis (which may be useful in disease evaluation). This review is based on a talk presented during the 2015 Grover Conference and highlights the relevant literature describing novel methods to phenotype pulmonary arterial hypertension patients by using approaches that involve the pulmonary and systemic (peripheral) vasculature. In particular, abnormalities in metabolism, the pulmonary and peripheral circulation, and exhaled breath in PH may help identify phenotypes that can be the basis for a precision-medicine approach to PH management. These approaches may also have a broader scope and may contribute to a better understanding of other diseases, such as asthma, diabetes, and cancer.

Volatile organic compounds in plasma for the diagnosis of esophageal adenocarcinoma: a pilot study.

BACKGROUND AND AIMS: A noninvasive screening test that can detect esophageal adenocarcinoma (EAC) at an earlier stage could improve the prognosis associated with EAC. The role of plasma volatile organic compounds (VOCs) for the diagnosis of EAC has not been previously studied. METHODS: Plasma samples were collected from subjects with EAC and GERD before endoscopy. Twenty-two preselected VOCs were analyzed with selected ion flow tube mass spectrometry. RESULTS: The headspaces from 39 plasma samples (20 EAC, 19 GERD) were analyzed. The levels of 9 VOCs (acetonitrile, acrylonitrile, carbon disulfide, isoprene, 1-heptene, 3-methylhexane, [E]-2-nonene, hydrogen sulfide, and triethylamine) were significantly altered in EAC patients compared with GERD patients. A multivariable logistic regression analysis was performed to build a model for the prediction of EAC. The model identified patients with EAC with an area under the curve of 0.83 (95% confidence interval, 0.67-0.98). CONCLUSIONS: Plasma VOCs may be useful in diagnosing EAC. Larger studies are needed to confirm our pilot study observations.

Treatment Efficacy of Integrative Family and Systems Treatment (I-FAST) With and Without Consultation: The Role of Model Training in the Sustainability of Evidence-Based Family Treatments.

This study examined the efficacy of the Integrative Family and Systems Treatment (I-FAST) training model that seeks to support development of model expertise within the agency in the context of facilitating the sustainability of evidence-based family treatment within community mental health settings. A quasi-experimental design was used to examine treatment outcomes of I-FAST among agencies that received ongoing Consultation and agencies that received No Consultation upon completion of I-FAST training. χ (2) analyses and independent samples t test analyses showed that there were no significant differences between the two groups on clients who had achieved reliable change on Problem Severity and Functioning based on parents' assessments. Significance of this study is discussed in the context of the role of evidence-based family therapy (EBFT) training in facilitating its sustainability in community mental health settings.

Isoprene in the Exhaled Breath is a Novel Biomarker for Advanced Fibrosis in Patients with Chronic Liver Disease: A Pilot Study.

OBJECTIVES: Analysis of volatile organic compounds (VOCs) in the exhaled breath can identify markers for alcoholic and nonalcoholic fatty liver disease. The aim of this pilot study was to investigate the utility of breath VOCs measured by mass spectrometry to diagnose advanced fibrosis in patients with chronic liver disease (CLD). METHODS: Patients undergoing liver biopsy were recruited. Fibrosis was determined by an experienced pathologist (F0-4) and advanced fibrosis was defined as F3-4. Exhaled breath and plasma samples were collected on the same day of the biopsy. Selective ion flow tube mass spectrometry (SIFT-MS) was used to analyze breath samples. Bonferroni correction was applied to decrease the false discovery rate. RESULTS: In all, 61 patients were included with a mean age of 50.7±9.9 years and 57% were male. Twenty patients (33%) had advanced fibrosis (F3-4), 44% had chronic hepatitis C, 30% had nonalcoholic fatty liver disease, and 26% had other CLD. SIFT-MS analysis of exhaled breath revealed that patients with advanced fibrosis had significantly lower values of six compounds compared with those without advanced fibrosis, P value <0.002 for all. Isoprene was found to have the highest accuracy for the prediction of advanced fibrosis with an area under the receiver operating characteristics curve of 0.855 (95% confidence interval: 0.762, 0.948). The median breath isoprene level in patients with F3-4 was 13.5[8.7, 24.7] p.p.b. compared with 40.4[26.2, 54.1] for those with F0-2, P value <0.001. Isoprene is an endogenous VOC that is a byproduct of cholesterol biosynthesis. CONCLUSIONS: Isoprene is a potential biomarker for advanced fibrosis that deserves further validation.

Analysis of breath volatile organic compounds in children with chronic liver disease compared to healthy controls.

Breath testing is increasingly being used as a non-invasive diagnostic tool for disease states across medicine. The purpose of this study was to compare the levels of volatile organic compounds (VOCs) as measured by mass spectrometry in healthy children and children with chronic liver disease (CLD). Patients between the ages of 6 and 21 were recruited for the study. Control subjects were recruited from a general pediatric population during well-child visits, while patients with CLD were recruited from pediatric gastroenterology clinic visits. The diagnosis of CLD was confirmed by clinical, laboratory, and/or histologic data. A single exhaled breath was collected and analyzed by means of selected-ion flow-tube mass spectrometry per protocol. A total of 104 patients were included in the study (49 with CLD and 55 healthy controls). Of the patients with CLD, 20 had advanced liver fibrosis (F3-F4). In the CLD cohort, levels of exhaled 1-decene, 1-heptene, 1-octene and 3 methylhexane were found to be significantly higher when compared to the control population (p < 0.001, p = 0.035, p < 0.001 and p = 0.004, respectively). Exhaled 1-nonene, (E)-2-nonene, and dimethyl sulfide levels were found to be significantly lower in patients with CLD patients when compared to controls (p < 0.001, p < 0.001 and p = 0.007, respectively). By utilizing a combination of five of the VOCs, the accuracy for predicting the presence of CLD was excellent (AUROC = 0.97). Our study demonstrates that children with CLD have a unique pattern of exhaled VOCs. Utilization of a combination of these VOCs represents a promising non-invasive diagnostic tool and may provide further insight into the pathophysiologic processes and pathways leading to pediatric liver disease. Further analysis of these compounds in external cohorts are needed to validate our findings.

Volatile Organic Compounds in Urine for Noninvasive Diagnosis of Malignant Biliary Strictures: A Pilot Study.

BACKGROUND: The use of volatile organic compounds (VOCs) in bile was recently studied and appeared promising for diagnosis of malignancy. Noninvasive diagnosis of malignant biliary strictures by using VOCs in urine has not been studied. AIM: To identify potential VOCs in urine to diagnose malignant biliary strictures. METHODS: In this prospective cross-sectional study, urine was obtained immediately prior to ERCP from consecutive patients with biliary strictures. Selected-ion flow-tube mass spectrometry was used to analyze the concentration of VOCs in urine samples. RESULTS: Fifty-four patients with biliary strictures were enrolled. Fifteen patients had malignant stricture [six cholangiocarcinoma (CCA) and nine pancreatic cancer], and 39 patients had benign strictures [10 primary sclerosing cholangitis (PSC) and 29 with benign biliary conditions including chronic pancreatitis and papillary stenosis]. The concentration of several compounds (ethanol and 2-propanol) was significantly different in patients with malignant compared with benign biliary strictures (p < 0.05). Using receiver operating characteristic curve analysis, we developed a model for the diagnosis of malignant biliary strictures adjusted for age and gender based on VOC levels of 2-propranol, carbon disulfide, and trimethyl amine (TMA). The model [-2.4191 * log(2-propanol) + 1.1617 * log(TMA) - 1.2172 * log(carbon disulfide)] ≥ 7.73 identified the patients with malignant biliary stricture [area under the curve (AUC = 0.83)], with 93.3 % sensitivity and 61.5 % specificity (p = 0.009). Comparing patients with CCA and PSC, the model [38.864 * log(ethane) - 3.989 * log(1-octene)] ≤ 169.9 could identify CCA with 80 % sensitivity and 100 % specificity (AUC = 0.9). CONCLUSIONS: Measurement of VOCs in urine may diagnose malignant biliary strictures noninvasively.