Analysis of exhaled breath for disease detection

Annual Review of Analytical Chemistry

Volumn 7, Issue , 2014, Pages 455-482

  Amann, Anton ^a,b   Miekisch, Wolfram ^c   Schubert, Jochen ^c   Buszewski, Bogusław ^d   Ligor, Tomasz ^d   Jezierski, Tadeusz ^e   Pleil, Joachim ^f   Risby, Terence ^g  

^a UNIVERSITY OF INNSBRUCK   (Austria)

^b INNSBRUCK MEDICAL UNIVERSITY   (Austria)

^c UNIVERSITY OF ROSTOCK   (Germany)

^d NICOLAUS COPERNICUS UNIVERSITY   (Poland)

^e INSTITUTE OF GENETICS AND ANIMAL BREEDING   (Poland)

^f U S ENVIRONMENTAL PROTECTION AGENCY   (United States)

^g The Johns Hopkins University   (United States)

Author keywords

Environmental health; Gas chromatography; Human exposome; Ion mobility spectrometry; Laser spectrometry; Personalized medicine; Preclinical effects; Proton transfer reaction time of flight mass spectrometry

Indexed keywords

GAS CHROMATOGRAPHY; MASS SPECTROMETRY; PULMONARY DISEASES;

ENVIRONMENTAL HEALTH; HUMAN EXPOSOME; ION MOBILITY SPECTROMETRY; LASER SPECTROMETRY; PERSONALIZED MEDICINES; PRECLINICAL EFFECTS; TIME OF FLIGHT MASS SPECTROMETRY;

METABOLITES;

BIOLOGICAL MARKER;

BREATH ANALYSIS; DIAGNOSTIC TEST; DISEASES; EXHALATION; HUMAN; MASS FRAGMENTOGRAPHY; PHYSIOLOGY; PROCEDURES;

BIOMARKERS; BREATH TESTS; DIAGNOSTIC TESTS, ROUTINE; DISEASE; EXHALATION; GAS CHROMATOGRAPHY-MASS SPECTROMETRY; HUMANS;

EID: 84904338175     PISSN: 19361327     EISSN: 19361335     Source Type: Book Series    
DOI: 10.1146/annurev-anchem-071213-020043     Document Type: Review

References (218)

1. Phillips M. 1992. Breath tests in medicine. Sci. Am. 267:74-79 (Pubitemid 23236501)
2. Baumbach JI, Vautz W, Ruzsanyi V, Freitag L. 2005. Metabolites in human breath: ion mobility spectrometers as diagnostic tools for lung diseases. See Ref. 217, pp. 53-66
3. Buszewski B, Kesy M, Ligor T, Amann A. 2007. Human exhaled air analytics: biomarkers of diseases. Biomed. Chromatogr. 21:553-66 (Pubitemid 46937852)
4. Amann A, Smith D, eds. 2013. Volatile Biomarkers: Non-Invasive Diagnosis in Physiology and Medicine. Amsterdam: Elsevier
5. Solga SF, Risby TH. 2013. Issues and challenges in human breath research: perspectives from our experience. See Ref. 4, pp. 19-24
6. Pleil JD, Stiegel MA, Risby TH. 2013. Clinical breath analysis: discriminating between human endogenous compounds and exogenous (environmental) chemical confounders. J. Breath Res. 7:1-11
7. Kazui M, Andreoni KA, Norris EJ, Klein AS, Burdick JF, et al. 1992. Breath ethane: a specific indicator of free-radical-mediated lipid peroxidation following reperfusion of the ischemic liver. Free Radic. Biol. Med. 13:509-15
8. Risby TH, Maley W, Scott RP, Bulkley GB, Kazui M, et al. 1994. Evidence for free radical-mediated lipid peroxidation at reperfusion of human orthotopic liver transplants. Surgery 115:94-101
9. Kazui M, Andreoni KA, Williams GM, Perler BA, Bulkley GB, et al. 1994. Visceral lipid peroxidation occurs at reperfusion after supraceliac aortic cross-clamping. J. Vasc. Surg. 19:473-77 (Pubitemid 24093981)
10. Andreoni KA, Kazui M, Cameron DE, Nyhan D, Sehnert SS, et al. 1999. Ethane: a marker of lipid peroxidation during cardiopulmonary bypass in humans. Free Radic. Biol. Med. 26:439-45 (Pubitemid 29013476)
11. Pabst F, Miekisch W, Fuchs P, Kischkel S, Schubert JK. 2007. Monitoring of oxidative and metabolic stress during cardiac surgery by means of breath biomarkers: an observational study. J. Cardiothorac. Surg. 2:37
12. Brown RH, Wagner EM, Cope KA, Risby TH. 2009. Propofol and in vivo oxidative stress: effects of preservative. J. Breath Res. 3:016003
13. King J, Mochalski P, Kupferthaler A, Unterkofler K, Koc H, et al. 2010. Dynamic profiles of volatile organic compounds in exhaled breath as determined by a coupled PTR-MS/GC-MS study. Physiol. Meas. 31:1169-84
14. Amann A, Telser S, Hofer L, Schmid A, Hinterhuber H. 2005. Exhaled breath gas as a biochemical probe during sleep. See Ref. 217, pp. 305-16
15. King J, KupferthalerA, Frauscher B, HacknerH, UnterkoflerK, et al. 2012. Measurement of endogenous acetone and isoprene in exhaled breath during sleep. Physiol. Meas. 33:413-28
16. Teranishi R, Mon TR, Robinson AB, Cary P, Pauling L. 1972. Gas chromatography of volatiles from breath and urine. Anal. Chem. 44:18-20
17. Mueller J. 1898. U ber die Ausscheidungsstatten des Acetons und die Bestimmung desselben in der Athemluft und den Hautausd unstungen des Menschen. Arch. Exp. Pathol. Pharmacol. 40:315-62
18. Henderson MJ, Karger BA, Wren Shall GA. 1952. Acetone in the breath: a study of acetone exhalation in diabetic and nondiabetic human subjects. Diabetes 1:188-93
19. McKee HC, Rhoades JW, Campbell J, Gross AL. 1962. Acetonitrile in body fluids related to smoking. Public Health Rep. 77:553-54
20. Bajtarevic A, Ager C, Pienz M, KlieberM, Schwarz K, et al. 2009. Noninvasive detection of lung cancer by analysis of exhaled breath. BMC Cancer 9:348
21. Rooth G, Ostenson S. 1966. Acetone in alveolar air, and the control of diabetes. Lancet 2:1102-5
22. Simenhoff ML, Burke JF, Saukkonen JJ, Ordinario AT, Doty R. 1977. Biochemical profile or uremic breath. N. Engl. J. Med. 297:132-35
23. Conkle JP, Camp BJ, Welch BE. 1975. Trace composition of human respiratory gas. Arch. Environ. Health 30:290-95
24. Jansson BO, Larsson BT. 1969. Analysis of organic compounds in human breath by gas chromatographymass spectrometry. J. Lab. Clin. Med. 74:961-66
25. Gelmont D, Stein RA, Mead JF. 1981. Isoprene-the main hydrocarbon in human breath. Biochem. Biophys. Res. Commun. 99:1456-60 (Pubitemid 12242937)
26. Kushch I, Arendacka B, Stolc S, Mochalski P, Filipiak W, et al. 2008. Breath isoprene: aspects of normal physiology related to age, gender and cholesterol profile as determined in a proton transfer reactionmass spectrometry study. Clin. Chem. Lab. Med. 46:1011-18 (Pubitemid 352000486)
27. King J, Kupferthaler A, Unterkofler K, Koc H, Teschl S, et al. 2009. Isoprene and acetone concentration profiles during exercise on an ergometer. J. Breath Res. 3:027006
28. Manolis A. 1983. The diagnostic potential of breath analysis. Clin. Chem. 29:5-15 (Pubitemid 13167610)
29. PhillipsM, Herrera J, Krishnan S, Zain M, Greenberg J, Cataneo RN. 1999. Variation in volatile organic compounds in the breath of normal humans. J. Chromatogr. B 729:75-88 (Pubitemid 29264111)
30. PhillipsM, Gleeson K, Hughes JM, Greenberg J, Cataneo RN, et al. 1999. Volatile organic compounds in breath as markers of lung cancer: a cross-sectional study. Lancet 353:1930-33 (Pubitemid 29255706)
31. Taucher J, HanselA, JordanA, Fall R, Futrell JH, LindingerW. 1997. Detection of isoprene in expired air from human subjects using proton-transfer-reaction mass spectrometry. Rapid Commun. Mass Spectrom. 11:1230-34 (Pubitemid 27324630)
32. Spanel P, Smith D. 2000. Selected ion flow tube mass spectrometry analyses of stable isotopes in water: isotopic composition of H3O+ and H3O+ (H2O)3 ions in exchange reactions with water vapor. J. Am. Soc. Mass Spectrom. 11:866-75 (Pubitemid 34532580)
33. Risby TH, Tittel FK. 2010. Current status of midinfrared quantum and interband cascade lasers for clinical breath analysis. Opt. Eng. 49:111123
34. Ruzsanyi V, Baumbach JI, Sielemann S, Litterst P, Westhoff M, Freitag L. 2005. Detection of human metabolites using multi-capillary columns coupled to ion mobility spectrometers. J. Chromatogr. A 1084:145-51 (Pubitemid 40966921)
35. King J, Unterkofler K, Teschl G, Teschl S, Mochalski P, et al. 2012. A modeling-based evaluation of isothermal rebreathing for breath gas analyses of highly soluble volatile organic compounds. J. Breath Res. 6:016005
36. Spanel P, Smith D. 2007. Selected ion flow tube mass spectrometry for on-line trace gas analysis in biology and medicine. Eur. J. Mass Spectrom. 13:77-82
37. King J, Koc H, Unterkofler K, Teschl G, Teschl S, et al. 2013. Physiological modeling for analysis of exhaled breath. See Ref. 4, pp. 27-46
38. Parameswaran KR, Rosen DI, Allen MG, Ganz AM, Risby TH. 2009. Off-axis integrated cavity output spectroscopy with a mid-infrared interband cascade laser for real-time breath ethane measurements. Appl. Opt. 48:B73-79
39. Shorter JH, Nelson DD, McManus JB, ZahniserMS, Sama SR, Milton DK. 2011. Clinical study of multiple breath biomarkers of asthma and COPD (NO, CO2, CO andN2O) by infrared laser spectroscopy. J. Breath Res. 5:037108
40. Mochalski P, Rudnicka J, Agapiou A, Statheropoulos M, Amann A, Buszewski B. 2013. Near real-time VOCs analysis using an aspiration ion mobility spectrometer. J. Breath Res. 7:026002
41. Ruzsanyi V, Fischer L, Herbig J, Ager C, Amann A. 2013. Multi-capillary-column proton-transferreaction time-of-flight mass spectrometry. J. Chromatogr. A 1316:112-18
42. BernierUR, BoothMM, Yost RA. 1999. Analysis of human skin emanations by gas chromatography/mass spectrometry. 1. Thermal desorption of attractants for the yellow fever mosquito (Aedes aegypti ) from handled glass beads. Anal. Chem. 71:1-7 (Pubitemid 29029499)
43. Bernier UR, Kline DL, Barnard DR, Schreck CE, Yost RA. 2000. Analysis of human skin emanations by gas chromatography/mass spectrometry. 2. Identification of volatile compounds that are candidate attractants for the yellow fever mosquito (Aedes aegypti ). Anal. Chem. 72:747-56 (Pubitemid 30111515)
44. Gallagher M, Wysocki CJ, Leyden JJ, Spielman AI, Sun X, Preti G. 2008. Analyses of volatile organic compounds from human skin. Br. J. Dermatol. 159:780-91
45. Ruzsanyi V, Mochalski P, Schmid A, Wiesenhofer H, KlieberM, et al. 2012. Ion mobility spectrometry for detection of skin volatiles. J. Chromatogr. B 911:84-92
46. Wagenstaller M, Buettner A. 2013. Characterization of odorants in human urine using a combined chemo-analytical and human-sensory approach: a potential diagnostic strategy. Metabolomics 9:9-20
47. Mochalski P, King J, Klieber M, Unterkofler K, Hinterhuber H, et al. 2013. Blood and breath levels of selected volatile organic compounds in healthy volunteers. Analyst 138:2134-45
48. Larsson BT. 1965. Gas chromatography of organic volatiles in human breath and saliva. Acta Chem. Scand. 19:159-64
49. Lochner A, Weisner S, Zlatkis A, Middleditch BS. 1986. Gas chromatographic-mass spectrometric analysis of volatile constituents in saliva. J. Chromatogr. 378:267-82 (Pubitemid 16061517)
50. Soini HA, Klouckova I, Wiesler D, Oberzaucher E, Grammer K, et al. 2010. Analysis of volatile organic compounds in human saliva by a static sorptive extraction method and gas chromatography-mass spectrometry. J. Chem. Ecol. 36:1035-42
51. Al-Kateb H, de Lacy Costello B, Ratcliffe N. 2013. An investigation of volatile organic compounds from the saliva of healthy individuals using headspace-trap/GC-MS. J. Breath Res. 7:036004
52. Buettner A. 2007. A selective and sensitive approach to characterize odour-active and volatile constituents in small-scale human milk samples. Flavour Fragr. J. 22:465-73 (Pubitemid 350162236)
53. Kim SR, Halden RU, Buckley TJ. 2007. Volatile organic compounds in human milk: methods and measurements. Environ. Sci. Technol. 41:1662-67 (Pubitemid 46362468)
54. de Lacy Costello B, Ratcliffe NM. 2013. Volatile organic compounds (VOCs) found in urine and stool. See Ref. 4, pp. 405-62
55. de Lacy Costello B, Amann A, Al-Kateb H, Flynn C, Filipiak W, Ratcliffe NM. 2013. A review of the volatiles from the healthy human body. J. Breath Res. 8:014001
56. PhillipsM, Altorki N, Austin JH, Cameron RB, Cataneo RN, et al. 2008. Detection of lung cancer using weighted digital analysis of breath biomarkers. Clin. Chim. Acta 393:76-84
57. Filipiak W, Ruzsanyi V, Mochalski P, Filipiak A, Bajtarevic A, et al. 2012. Dependence of exhaled breath composition on exogenous factors, smoking habits and exposure to air pollutants. J. Breath Res. 6:036008
58. Mochalski P, Unterkofler K, HinterhuberH, Amann A. 2014. Monitoring of selected skin-borne volatile markers of entrapped humans by selective reagent ionization time of flight mass spectrometry in NO+ mode. Anal. Chem. 86:3915-23
59. Mochalski P, Krapf K, Ager C, Wiesenhofer H, Agapiou A, et al. 2012. Temporal profiling of human urineVOCs and its potential role under the ruins of collapsed buildings. Toxicol. Mech.Methods 22:502-11
60. Filipiak W, Sponring A, Filipiak A, Ager C, Schubert J, et al. 2010. TD-GC-MS analysis of volatile metabolites of human lung cancer and normal cells in vitro. Cancer Epidemiol. Biomarkers Prev. 19:182-95
61. FilipiakW, Sponring A, BaurMM, Ager C, Filipiak A, et al. 2012. Characterization of volatile metabolites taken up by or released from Streptococcus pneumoniae and Haemophilus influenzae by using GC-MS. Microbiology 158:3044-53
62. Filipiak W, Sponring A, Baur MM, Filipiak A, Ager C, et al. 2012. Molecular analysis of volatile metabolites released specifically by Staphylococcus aureus and Pseudomonas aeruginosa. BMC Microbiol. 12:113
63. Filipiak W, Sponring A, Mikoviny T, Ager C, Schubert J, et al. 2008. Release of volatile organic compounds (VOCs) from the lung cancer cell line CALU-1 in vitro. Cancer Cell Int. 8:17
64. Sponring A, Filipiak W, Mikoviny T, Ager C, Schubert J, et al. 2009. Release of volatile organic compounds from the lung cancer cell line NCI-H2087 in vitro. Anticancer Res. 29:419-26
65. Sponring A, Filipiak W, Ager C, Schubert J, Miekisch W, et al. 2010. Analysis of volatile organic compounds (VOCs) in the headspace of NCI-H1666 lung cancer cells. Cancer Biomarkers A 7:153-61
66. Filipiak W, Filipiak A, Sponring A, Schmid T, Zelger B, et al. 2014. Comparative analyses of volatile organic compounds (VOCs) from patients, tumors and transformed cell lines for the validation of lung cancer-derived breath markers. J. Breath Res. 8:027111
67. Pleil JD, StiegelM. 2013. Evolution of environmental exposure science: using breath-borne biomarkers for "discovery" of the human exposome. Anal. Chem. 85:9984-90
68. Erhart S, Amann A, Haberlandt E, Edlinger G, Schmid A, et al. 2009. 3-Heptanone as a potential new marker for valproic acid therapy. J. Breath Res. 3:016004
69. Pleil JD, Smith LB, Zelnick SD. 2000. Personal exposure to JP-8 jet fuel vapors and exhaust at air force bases. Environ. Health Perspect. 108:183-92 (Pubitemid 30195574)
70. Pleil JD, Kim D, Prah JD, Rappaport SM. 2007. Exposure reconstruction for reducing uncertainty in risk assessment: example using MTBE biomarkers and a simple pharmacokinetic model. Biomarkers 12:331-48 (Pubitemid 46952297)
71. Ghimenti S, Di Francesco F, OnorM, Stiegel MA, TrivellaMG, et al. 2013. Post-operative elimination of sevoflurane anesthetic and hexafluoroisopropanolmetabolite in exhaled breath: pharmacokineticmodels for assessing liver function. J. Breath Res. 7:036001
72. KimD, AndersenME, Pleil JD, Nylander-French LA, Prah JD. 2007. Refined PBPK model of aggregate exposure to methyl tertiary-butyl ether. Toxicol. Lett. 169:222-35 (Pubitemid 46437429)
73. King J, Koc H, Unterkofler K, Mochalski P, Kupferthaler A, et al. 2010. Physiological modeling of isoprene dynamics in exhaled breath. J. Theor. Biol. 267:626-37
74. Koc H, King J, Teschl G, Unterkofler K, Teschl S, et al. 2011. The role of mathematical modeling in VOC analysis using isoprene as a prototypic example. J. Breath Res. 5:037102
75. Pleil JD, Lindstrom AB. 1997. Exhaled human breath measurement method for assessing exposure to halogenated volatile organic compounds. Clin. Chem. 43:723-30 (Pubitemid 27208772)
76. Pleil JD, Lindstrom AB. 1998. Sample timing and mathematical considerations for modeling breath elimination of volatile organic compounds. Risk Anal. 18:585-602
77. Pleil JD. 2008. Role of exhaled breath biomarkers in environmental health science. J. Toxicol. Environ. Health. B 11:613-29
78. Beauchamp J, Kirsch F, Buettner A. 2010. Real-time breath gas analysis for pharmacokinetics:monitoring exhaled breath by on-line proton-transfer- reaction mass spectrometry after ingestion of eucalyptolcontaining capsules. J. Breath Res. 4:026006
79. LindstromAB, Pleil JD, BerkoffDC. 1997. Alveolar breath sampling and analysis to assess trihalomethane exposures during competitive swimming training. Environ. Health Perspect. 105:636-42 (Pubitemid 27405812)
80. Zhu J, Jimenez-Diaz J, Bean HD, DaphtaryNA, Aliyeva MI, et al. 2013. Robust detection of P. aeruginosa and S. aureus acute lung infections by secondary electrospray ionization-mass spectrometry (SESI-MS) breathprinting: from initial infection to clearance. J. Breath Res. 7:037106
81. Schubert R, Schwoebel H, Mau-Moeller A, Behrens M, Fuchs P, et al. 2012. Metabolic monitoring and assessment of anaerobic threshold by means of breath biomarkers. Metabolomics 8:1069-80
82. King J, Mochalski P, Unterkofler K, Teschl G, KlieberM, et al. 2012. Breath isoprene: muscle dystrophy patients support the concept of a pool of isoprene in the periphery of the human body. Biochem. Biophys. Res. Commun. 423:526-30
83. Farhi LE. 1967. Elimination of inert gas by the lung. Respir. Physiol. 3:1-11
84. Mochalski P, King J, Kupferthaler A, Unterkofler K, Hinterhuber H, Amann A. 2011. Measurement of isoprene solubility in water, human blood and plasma by multiple headspace extraction gas chromatography coupled with solid phase microextraction. J. Breath Res. 5:046010
85. Mochalski P, King J, Kupferthaler A, Unterkofler K, HinterhuberH, Amann A. 2012. Human blood and plasma partition coefficients for C4-C8 n-alkanes, isoalkanes, and 1-alkenes. Int. J. Toxicol. 31:267-75
86. Filser JG, Csanady GA, Denk B, Hartmann M, Kauffmann A, et al. 1996. Toxicokinetics of isoprene in rodents and humans. Toxicology 113:278-87 (Pubitemid 26364104)
87. Ezzeldin HH, Acosta EP, Mattison LK, Fourie J, Modak A, Diasio RB. 2009. 13C-5-FU breath test current status and future directions: a comprehensive review. J. Breath Res. 3:047002
88. Opdam FL, Modak AS, Gelderblom H, Guchelaar HJ. 2013. Breath tests to phenotype drug disposition in oncology. Clin. Pharmacokinet. 52:919-28
89. Modak A. 2009. Breath tests with 13C substrates. J. Breath Res. 3:040201
90. Desta Z, Modak A, Nguyen PD, Lemler SM, Kurogi Y, et al. 2009. Rapid identification of the hepatic cytochrome P450 2C19 activity using a novel and noninvasive [13C]pantoprazole breath test. J. Pharmacol. Exp. Ther. 329:297-305
91. Ingelman-Sundberg M. 2001. Genetic susceptibility to adverse effects of drugs and environmental toxicants. The role of the CYP family of enzymes. Mutat. Res. 482:11-19 (Pubitemid 32787077)
92. Ozsoylu S. 1996. End-tidal carbon monoxide and neonatal jaundice. J. Pediatr. 129:485-86 (Pubitemid 27484165)
93. Eisenmann A, Amann A, Said M, Datta B, Ledochowski M. 2008. Implementation and interpretation of hydrogen breath tests. J. Breath Res. 2:046002
94. de Lacy Costello BP, Ledochowski M, Ratcliffe NM. 2013. The importance of methane breath testing: a review. J. Breath Res. 7:024001
95. Tomikawa M, OguraK, IikuraK, YanagidaN, Sato S, et al. 2013. Asthma diagnosis and treatment -1005. Optimization for the withdrawal of inhaled corticosteroid treatment by monitoring fractional exhaled nitric oxide (feno) and lung functions. World Allergy Organ. J. 6(Suppl. 1):P5
96. Pike K, Selby A, Price S, Warner J, Connett G, et al. 2012. Exhaled nitric oxide monitoring does not reduce exacerbation frequency or inhaled corticosteroid dose in paediatric asthma: a randomised controlled trial. Clin. Respir. J. 7:204-13
97. Phillips M, Boehmer JP, Cataneo RN, Cheema T, Eisen HJ, et al. 2004. Prediction of heart transplant rejection with a breath test for markers of oxidative stress. Am. J. Cardiol. 94:1593-94 (Pubitemid 40268475)
98. Sehnert SS, Jiang L, Burdick JF, Risby TH. 2002. Breath biomarkers for detection of human liver diseases: preliminary study. Biomarkers 7:174-87 (Pubitemid 34413866)
99. Xue R, Dong L, Zhang S, Deng C, Liu T, et al. 2008. Investigation of volatile biomarkers in liver cancer blood using solid-phase microextraction and gas chromatography/mass spectrometry. Rapid Commun. Mass Spectrom. 22:1181-86 (Pubitemid 351600767)
100. Wzorek B, Mochalski P, Sliwka I, Amann A. 2010. Application of GC-MS with a SPME and thermal desorption technique for determination of dimethylamine and trimethylamine in gaseous samples for medical diagnostic purposes. J. Breath Res. 4:026002
101. Wehinger A, Schmid A, Mechtcheriakov S, Ledochowski M, Grabmer C, et al. 2007. Lung cancer detection by proton transfer reaction mass-spectrometric analysis of human breath gas. Int. J. Mass Spectrom. 265:49-59
102. Hakim M, Broza YY, Barash O, Peled N, Phillips M, et al. 2012. Volatile organic compounds of lung cancer and possible biochemical pathways. Chem. Rev. 112:5949-66
103. van de Kant KD, van der Sande LJ, Jobsis Q, van Schayck OC, Dompeling E. 2012. Clinical use of exhaled volatile organic compounds in pulmonary diseases: a systematic review. Respir. Res. 13:117
104. Paredi P, Kharitonov SA, Barnes PJ. 2000. Elevation of exhaled ethane concentration in asthma. Am. J. Respir. Crit. Care Med. 162:1450-54
105. Simpson JL, Wark PA. 2008. The role of exhaled nitric oxide and exhaled breath condensates in evaluating airway inflammation in asthma. Expert Opin. Med. Diagn. 2:607-20 (Pubitemid 351997851)
106. Modak A. 2013. An update on 13C-breath tests: the transition to acceptability into clinical practice. See Ref. 4, pp. 245-62
107. Liu S, Pleil JD. 1999. Method for liquid-liquid extraction of blood surrogates for assessing human exposure to jet fuel. J. Chromatogr. B 728:193-207 (Pubitemid 29248862)
108. Tu RH, Mitchell CS, Kay GG, Risby TH. 2004. Human exposure to the jet fuel, JP-8. Aviat. Space Environ. Med. 75:49-59 (Pubitemid 38040664)
109. Cope KA, Merritt WT, Krenzischek DA, Schaefer J, Bukowski J, et al. 2002. Phase II collaborative pilot study: preliminary analysis of central neural effects from exposure to volatile anesthetics in the PACU. J. Perianesth. Nurs. 17:240-50 (Pubitemid 40433755)
110. Pleil JD, Stiegel MA, Sobus JR. 2011. Breath biomarkers in environmental health science: exploring patterns in the human exposome. J. Breath Res. 5:046005
111. Pleil JD, StiegelMA, Sobus JR, Liu Q, MaddenMC. 2011. Observing the human exposome as reflected in breath biomarkers: heatmap data interpretation for environmental and intelligence research. J. Breath Res. 5:037104
112. Gilchrist FJ, Bright-Thomas RJ, Jones AM, Smith D, Spanel P, et al. 2013. Hydrogen cyanide concentrations in the breath of adult cystic fibrosis patients with and without Pseudomonas aeruginosa infection. J. Breath Res. 7:026010
113. Filipiak W, Sponring A, Filipiak A, Baur MM, Ager C, et al. 2013. Volatile organic compounds (VOCs) released by pathogenic microorganisms in vitro: potential breath biomarkers for early-stage diagnosis of disease. See Ref. 4, pp. 463-512
114. Lalazar G, Adar T, Ilan Y. 2009. Point-of-care continuous 13C-methacetin breath test improves decision making in acute liver disease: results of a pilot clinical trial. World J. Gastroenterol. 15:966-72
115. Giannini EG, Fasoli A, Borro P, Botta F, Malfatti F, et al. 2005. 13C-galactose breath test and 13Caminopyrine breath test for the study of liver function in chronic liver disease. Clin. Gastroenterol.Hepatol. 3:279-85 (Pubitemid 40568734)
116. Adrover R, Cocozzella D, Ridruejo E, Garcia A, Rome J, Podesta JJ. 2012. Breath-ammonia testing of healthy subjects and patients with cirrhosis. Dig. Dis. Sci. 57:189-95
117. Endre ZH, Pickering JW, Storer MK, Hu WP, Moorhead KT, et al. 2011. Breath ammonia and trimethylamine allow real-time monitoring of haemodialysis efficacy. Physiol. Meas. 32:115-30
118. Grabowska-Polanowska B, Faber J, Skowron M, Miarka P, Pietrzycka A, et al. 2013. Detection of potential CKD markers in breath using GCMS coupled with thermal desorptionmethod. J. Chromatogr. A 1301:179-89
119. Zschocke J, Kohlmueller D, Quak E, Meissner T, Hoffmann GF, Mayatepek E. 1999. Mild trimethylaminuria caused by common variants in FMO3 gene. Lancet 354:834-35 (Pubitemid 29415594)
120. Chalmers RA, Bain MD, Michelakakis H, Zschocke J, Iles RA. 2006. Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children. J. Inherit. Metab. Dis. 29:162-72
121. Alving K, Weitzberg E, Lundberg JM. 1993. Increased amount of nitric oxide in exhaled air of asthmatics. Eur. Respir. J. 6:1368-70 (Pubitemid 23329557)
122. Hogman M. 2012. Extended NO analysis in health and disease. J. Breath Res. 6:047103
123. Hogman M, Stromberg S, Schedin U, Frostell C, Hedenstierna G, Gustafsson LE. 1997. Nitric oxide from the human respiratory tract efficiently quantified by standardized single breath measurements. Acta Physiol. Scand. 159:345-46 (Pubitemid 27193344)
124. Silkoff PE, McClean PA, Slutsky AS, Furlott HG, Hoffstein E, et al. 1997. Marked flow-dependence of exhaled nitric oxide using a new technique to exclude nasal nitric oxide. Am. J. Respir. Crit. CareMed. 155:260-67 (Pubitemid 27053174)
125. Kharitonov S, Alving K, Barnes PJ. 1997. Exhaled and nasal nitric oxide measurements: recommendations. The European Respiratory Society Task Force. Eur. Respir. J. 10:1683-93 (Pubitemid 27311092)
126. Am. Thorac. Soc., Eur. Respir. Soc. 2005. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am. J. Respir. Crit. CareMed. 171:912-30
127. George SC, Hogman M, Permutt S, Silkoff PE. 2004. Modeling pulmonary nitric oxide exchange. J. Appl. Physiol. 96:831-39 (Pubitemid 38248651)
128. Van Berkel JJ, Dallinga JW, Moller GM, Godschalk RW, Moonen EJ, et al. 2010. A profile of volatile organic compounds in breath discriminates COPD patients from controls. Respir. Med. 104:557-63
129. Phillips M, Cataneo RN, Cummin AR, Gagliardi AJ, Gleeson K, et al. 2003. Detection of lung cancer with volatile markers in the breath. Chest 123:2115-23 (Pubitemid 36706741)
130. Westhoff M, Freitag PLL, Ruzsanyi V, Bader S, UrferW, Baumbach JI. 2005. Ionmobility spectrometry: a new method for the detection of lung cancer and airway infection in exhaled air? First results of a pilot study. Chest 128:155S
131. PhillipsM, Altorki N, Austin JH, Cameron RB, Cataneo RN, et al. 2007. Prediction of lung cancer using volatile biomarkers in breath. Cancer Biomark. A 3:95-109 (Pubitemid 47103811)
132. Hakim M, Broza YY, Barash O, Peled N, Phillips M, et al. 2012. Volatile organic compounds of lung cancer and possible biochemical pathways. Chem. Rev. 112:5949-66
133. Peng G, TischU, Adams O, HakimM, Shehada N, et al. 2009. Diagnosing lung cancer in exhaled breath using gold nanoparticles. Nat. Nanotechnol. 4:669-73
134. Haick H, Broza Y, Mochalski P, Ruzsanyi V, Amann A. 2014. Assessment, origin, and implementation of breath volatile cancer markers. Chem. Soc. Rev. 43:1423-49
135. Fuchs P, Loeseken C, Schubert JK, Miekisch W. 2010. Breath gas aldehydes as biomarkers of lung cancer. Int. J. Cancer 126:2663-70
136. Fuchs D, Jamnig H, Heininger P, KlieberM, Schroecksnadel S, et al. 2012. Decline of exhaled isoprene in lung cancer patients correlates with immune activation. J. Breath Res. 6:027101
137. Pounder RE, Ng D. 1995. The prevalence of Helicobacter pylori infection in different countries. Aliment Pharmacol. Ther. 9(Suppl. 2):33-39
138. Selgrad M, Malfertheiner P. 2008. New strategies for Helicobacter pylori eradication. Curr. Opin. Pharmacol. 8:593-97
139. Xu ZQ, Broza YY, Ionsecu R, Tisch U, Ding L, et al. 2013. A nanomaterial-based breath test for distinguishing gastric cancer from benign gastric conditions. Br. J. Cancer 108:941-50
140. Wisthaler A, Weschler CJ. 2010. Reactions of ozone with human skin lipids: sources of carbonyls, dicarbonyls, and hydroxycarbonyls in indoor air. Proc. Natl. Acad. Sci. USA 107:6568-75
141. Lieberman M, Hochstein P. 1966. Ethylene formation in rat liver microsomes. Science 152:213-14
142. Lieberman M, Mapson LW. 1964. Genesis and biogenesis of ethylene. Nature 204:343-45
143. Meigh DF. 1962. Problems of ethylene metabolism. Nature 196:345-47
144. Riely CA, Cohen G, Lieberma M. 1974. Ethane evolution: new index of lipid peroxidation. Science 183:208-10
145. Dumelin EE, Tappel AL. 1977. Hydrocarbon gases produced during in vitro peroxidation of polyunsaturated fatty acids and decomposition of preformed hydroperoxides. Lipids 12:894-900 (Pubitemid 8230587)
146. Lawrence GD, CohenG. 1982. Ethane exhalation as an index of in vivo lipid peroxidation: concentrating ethane from a breath collection chamber. Anal. Biochem. 122:283-90 (Pubitemid 12053350)
147. Lawrence GD, CohenG. 1984. Concentrating ethane from breath tomonitor lipid peroxidation in vivo. Methods Enzymol. 105:305-11 (Pubitemid 14165391)
148. Dillard CJ, Dumelin EE, Tappel AL. 1977. Effect of dietary vitamin E on expiration of pentane and ethane by the rat. Lipids 12:109-14 (Pubitemid 8036652)
149. Sagai M, Ichinose T. 1980. Age-related changes in lipid peroxidation as measured by ethane, ethylene, butane and pentane in respired gases of rats. Life Sci. 27:731-38 (Pubitemid 11192176)
150. Risby TH, Jiang L, Stoll S, Ingram D, Spangler E, et al. 1999. Breath ethane as a marker of reactive oxygen species during manipulation of diet and oxygen tension in rats. J. Appl. Physiol. 86:617-22 (Pubitemid 29075816)
151. Kohlmuller D, Kochen W. 1993. Is n-pentane really an index of lipid peroxidation in humans and animals? A methodological reevaluation. Anal. Biochem. 210:268-76 (Pubitemid 23171017)
152. Deneris ES, Stein RA, Mead JF. 1985. Acid-catalyzed formation of isoprene from a mevalonate-derived product using a rat liver cytosolic fraction. J. Biol. Chem. 260:1382-85 (Pubitemid 15144148)
153. Risby TH. 2002. Volatile organic compounds as markers in normal and diseased states. See Ref. 218, pp. 113-22
154. Van GossumA, Decuyper J. 1989. Breath alkanes as an index of lipid peroxidation. Eur. Respir. J. 2:787-91
155. Kneepkens CM, Ferreira C, Lepage G, Roy CC. 1992. The hydrocarbon breath test in the study of lipid peroxidation: principles and practice. Clin. Investig. Med. 15:163-86
156. Kneepkens CM, Lepage G, Roy CC. 1994. The potential of the hydrocarbon breath test as a measure of lipid peroxidation. Free Radic. Biol. Med. 17:127-60 (Pubitemid 24217183)
157. Risby TH, Sehnert SS. 1999. Clinical application of breath biomarkers of oxidative stress status. Free Radic. Biol. Med. 27:1182-92 (Pubitemid 30001477)
158. Paredi P, Kharitonov SA, Barnes PJ. 2002. Analysis of expired air for oxidation products. Am. J. Respir. Crit. Care Med. 166:S31-37 (Pubitemid 36015934)
159. BrownRH, RisbyTH. 2002. Monitoring distant organ reperfusion injury by volatile organic compounds. See Ref. 218, pp. 281-306
160. Miekisch W, Schubert JK, Noeldge-SchomburgGF. 2004. Diagnostic potential of breath analysis: focus on volatile organic compounds. Clin. Chim. Acta 347:25-39 (Pubitemid 39099603)
161. Gorham KA, Sulbaek Andersen MP, Meinardi S, Delfino RJ, et al. 2009. Ethane and n-pentane in exhaled breath are biomarkers of exposure not effect. Biomarkers 14:17-25
162. Dryahina K, Spanel P, Pospisilova V, Sovova K, Hrdlicka L, et al. 2013. Quantification of pentane in exhaled breath, a potential biomarker of bowel disease, using selected ion flow tube mass spectrometry. Rapid Commun. Mass Spectrom. 27:1983-92
163. Harren FJM, Berkelmans R, KuiperK, Hekkert ST, Scheepers P, et al. 1999. On-line laser photoacoustic detection of ethene in exhaled air as biomarker of ultraviolet radiation damage of the human skin. Appl. Phys. Lett. 74:1761-63 (Pubitemid 129310631)
164. Patterson CS, McMillan LC, Stevenson K, Radhakrishnan K, Shiels PG, et al. 2007. Dynamic study of oxidative stress in renal dialysis patients based on breath ethane measured by optical spectroscopy. J. Breath Res. 1:026005
165. Thelen S, Miekisch W, Halmer D, Schubert J, Hering P, Murtz M. 2008. Intercomparison of infrared cavity leak-out spectroscopy and gas chromatography-flame ionization for trace analysis of ethane. Anal. Chem. 80:2768-73 (Pubitemid 351556437)
166. Phillips M, Cataneo RN, Greenberg J, Gunawardena R, Naidu A, Rahbari-Oskoui F. 2000. Effect of age on the breath methylated alkane contour, a display of apparent new markers of oxidative stress. J. Lab. Clin. Med. 136:243-49
167. Poli D, Goldoni M, Corradi M, Acampa O, Carbognani P, et al. 2010. Determination of aldehydes in exhaled breath of patients with lung cancer by means of on-fiber-derivatisation SPME-GC/MS. J. Chromatogr. B 878:2643-51
168. Corradi M, Rubinstein I, Andreoli R, Manini P, Caglieri A, et al. 2003. Aldehydes in exhaled breath condensate of patients with chronic obstructive pulmonary disease.Am. J. Respir. Crit. CareMed. 167:1380-86 (Pubitemid 36609723)
169. Schubert JK, Miekisch W, Geiger K, Noldge-Schomburg GF. 2004. Breath analysis in critically ill patients: potential and limitations. Expert Rev. Mol. Diagn. 4:619-29 (Pubitemid 39220837)
170. Schubert JK, Miekisch W, Birken T, Geiger K, Noldge-Schomburg GF. 2005. Impact of inspired substance concentrations on the results of breath analysis in mechanically ventilated patients. Biomarkers 10:138-52 (Pubitemid 40916672)
171. Miekisch W, Kischkel S, Sawacki A, Liebau T, Mieth M, Schubert JK. 2008. Impact of sampling procedures on the results of breath analysis. J. Breath Res. 2:026007
172. Schwoebel H, Schubert R, Sklorz M, Kischkel S, Zimmermann R, et al. 2011. Phase-resolved real-time breath analysis during exercise by means of smart processing of PTR-MS data. Anal. Bioanal. Chem. 401:2079-91
173. Schubert JK, Spittler KH, Braun G, Geiger K, Guttmann J. 2001. CO2-controlled sampling of alveolar gas in mechanically ventilated patients. J. Appl. Physiol. 90:486-92 (Pubitemid 32118907)
174. Miekisch W, Hengstenberg A, Kischkel S, Beckmann U, Mieth M, Schubert JK. 2010. Construction and evaluation of a versatile CO2 controlled breath collection device. IEEE Sens. J. 10:211-15
175. Schubert JK, Esteban-Loos I, Geiger K, Guttmann J. 1999. In vivo evaluation of a newmethod for chemical analysis of volatile components in the respiratory gas of mechanically ventilated patients. Technol. Health Care 7:29-37 (Pubitemid 29130606)
176. Miekisch W, Schubert JK, Vagts DA, Geiger K. 2001. Analysis of volatile disease markers in blood. Clin. Chem. 47:1053-60 (Pubitemid 32493591)
177. Miekisch W, Fuchs P, Kamysek S, Neumann C, Schubert JK. 2008. Assessment of propofol concentrations in human breath and blood by means of HS-SPME-GC-MS. Clin. Chim. Acta 395:32-37
178. MiethM, Kischkel S, Schubert JK, Hein D, MiekischW. 2009. Multibed needle trap devices for on site sampling and preconcentration of volatile breath biomarkers. Anal. Chem. 81:5851-57
179. Mieth M, Schubert JK, Groger T, Sabel B, Kischkel S, et al. 2010. Automated needle trap heart-cut GC/MS and needle trap comprehensive two-dimensional GC/TOF-MS for breath gas analysis in the clinical environment. Anal. Chem. 82:2541-51
180. Trefz P, Kischkel S, Hein D, James ES, Schubert JK, MiekischW. 2012. Needle trap micro-extraction for VOC analysis: effects of packing materials and desorption parameters. J. Chromatogr. A 1219:29-38
181. Trefz P, Rosner L, Hein D, Schubert JK, MiekischW. 2013. Evaluation of needle trap micro-extraction and automatic alveolar sampling for point-of-care breath analysis. Anal. Bioanal. Chem. 405:3105-15
182. Kamysek S, Fuchs P, Schwoebel H, Roesner JP, Kischkel S, et al. 2011. Drug detection in breath: effects of pulmonary blood flow and cardiac output on propofol exhalation. Anal. Bioanal. Chem. 401:2093-102
183. Boshier PR, Cushnir JR, Mistry V, Knaggs A, Spanel P, et al. 2011. On-line, real time monitoring of exhaled trace gases by SIFT-MS in the perioperative setting: a feasibility study. Analyst 136:3233-37
184. Trefz P, Schmidt M, Oertel P, Obermeier J, Brock B, et al. 2013. Continuous real time breath gas monitoring in the clinical environment by proton-transfer-reaction-time-of-flight-mass spectrometry. Anal. Chem. 85:10321-29
185. Aghdassi E, Wendland BE, Steinhart AH, Wolman SL, Jeejeebhoy K, Allard JP. 2003. Antioxidant vitamin supplementation in Crohns disease decreases oxidative stress. a randomized controlled trial. Am. J. Gastroenterol. 98:348-53 (Pubitemid 36232384)
186. Scholpp J, Schubert JK, Miekisch W, Geiger K. 2002. Breath markers and soluble lipid peroxidation markers in critically ill patients. Clin. Chem. Lab. Med. 40:587-94 (Pubitemid 34855125)
187. Mendis S, Sobotka PA, Leja FL, Euler DE. 1995. Breath pentane and plasma lipid peroxides in ischemic heart disease. Free Radic. Biol. Med. 19:679-84
188. Weitz ZW, Birnbaum AJ, Sobotka PA, Zarling EJ, Skosey JL. 1991. High breath pentane concentrations during acute myocardial infarction. Lancet 337:933-35
189. Sobotka PA, Gupta DK, Lansky DM, Costanzo MR, Zarling EJ. 1994. Breath pentane is a marker of acute cardiac allograft rejection. J. Heart Lung Transplant. 13:224-29 (Pubitemid 24111712)
190. Olopade CO, ZakkarM, Swedler WI, Rubinstein I. 1997. Exhaled pentane levels in acute asthma. Chest 111:862-65 (Pubitemid 27171453)
191. Paredi P, Kharitonov SA, Leak D, Ward S, Cramer D, Barnes PJ. 2000. Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 162:369-73 (Pubitemid 30647168)
192. Olopade CO, Christon JA, ZakkarM, Hua C, SwedlerWI, et al. 1997. Exhaled pentane and nitric oxide levels in patients with obstructive sleep apnea. Chest 111:1500-4 (Pubitemid 27260072)
193. Schubert JK, Muller WP, Benzing A, GeigerK. 1998. Application of a newmethod for analysis of exhaled gas in critically ill patients. Intensive Care Med. 24:415-21 (Pubitemid 28274151)
194. Foster WM, Jiang L, Stetkiewicz PT, Risby TH. 1996. Breath isoprene: temporal changes in respiratory output after exposure to ozone. J. Appl. Physiol. 80:706-10 (Pubitemid 26061481)
195. Kischkel S, Miekisch W, Fuchs P, Schubert JK. 2012. Breath analysis during one-lung ventilation in cancer patients. Eur. Respir. J. 40:706-13
196. Holt DW, Johnston A, Ramsey JD. 1994. Breath pentane and heart rejection. J. Heart Lung Transplant. 13:1147-48
197. Studer SM, Orens JB, Rosas I, Krishnan JA, Cope KA, et al. 2001. Patterns and significance of exhaledbreath biomarkers in lung transplant recipients with acute allograft rejection. J. Heart Lung Transplant. 20:1158-66 (Pubitemid 33035077)
198. HarrisonGR, Critchley AD, Mayhew CA, Thompson JM. 2003. Real-time breath monitoring of propofol and its volatile metabolites during surgery using a novel mass spectrometric technique: a feasibility study. Br. J. Anaesth. 91:797-99 (Pubitemid 37508819)
199. Grossherr M, Hengstenberg A, Meier T, Dibbelt L, Igl BW, et al. 2009. Propofol concentration in exhaled air and arterial plasma in mechanically ventilated patients undergoing cardiac surgery. Br. J. Anaesth. 102:608-13
200. Furton KG, Myers LJ. 2001. The scientific foundation and efficacy of the use of canines as chemical detectors for explosives. Talanta 54:487-500 (Pubitemid 32405611)
201. Lorenzo N, Wan T, Harper RJ, Hsu YL, Chow M, et al. 2003. Laboratory and field experiments used to identify Canis lupus var. familiaris active odor signature chemicals from drugs, explosives, and humans. Anal. Bioanal. Chem. 376:1212-24 (Pubitemid 40871610)
202. Williams H, Pembroke A. 1989. Sniffer dogs in the melanoma clinic? Lancet 1:734
203. Church J, Williams H. 2001. Another sniffer dog for the clinic? Lancet 358:930
204. Pickel D, Manucy GP, Walker DB, Hall SB, Walker JC. 2004. Evidence for canine olfactory detection of melanoma. Appl. Anim. Behav. Sci. 89:107-16 (Pubitemid 39301104)
205. Willis CM, Church SM, Guest CM, Cook WA, McCarthy N, et al. 2004. Olfactory detection of human bladder cancer by dogs: proof of principle study. Br. Med. J 329:712
206. McCulloch M, Jezierski T, Broffman M, Hubbard A, Turner K, Janecki T. 2006. Diagnostic accuracy of canine scent detection in early-and late-stage lung and breast cancers. Integr. Cancer Ther. 5:30-39 (Pubitemid 43260792)
207. Horvath G, Jarverud GA, Jarverud S, Horvath I. 2008. Human ovarian carcinomas detected by specific odor. Integr. Cancer Ther. 7:76-80 (Pubitemid 351806533)
208. Gordon RT, Schatz CB, Myers LJ, KostyM, Gonczy C, et al. 2008. The use of canines in the detection of human cancers. J. Altern. Complement. Med. 14:61-67 (Pubitemid 351185428)
209. Cornu JN, Cancel-Tassin G, Ondet V, Girardet C, Cussenot O. 2011. Olfactory detection of prostate cancer by dogs sniffing urine: a step forward in early diagnosis. Eur. Neurol. 59:197-201
210. Sonoda H, Kohnoe S, Yamazato T, Satoh Y, Morizono G, et al. 2011. Colorectal cancer screening with odour material by canine scent detection. Gut 60:814-19
211. Ehmann R, Boedeker E, Friedrich U, Sagert J, Dippon J, et al. 2012. Canine scent detection in the diagnosis of lung cancer: revisiting a puzzling phenomenon. Eur. Respir. J. 39:669-76
212. Buszewski B, Ligor T, Jezierski T, Wenda-Piesik A, Walczak M, Rudnicka J. 2012. Identification of volatile lung cancermarkers by gas chromatography-mass spectrometry: comparison with discrimination by canines. Anal. Bioanal. Chem. 404:141-46
213. Buszewski B, Rudnicka J, Ligor T, Walczak M, Jezierski T, Amann A. 2012. Analytical and unconventional methods of cancer detection using odor. Trends Anal. Chem. 38:1-12
214. Vul E, Harris C, Winkielman P, Pashler H. 2009. Puzzlingly high correlations in fMRI studies of emotion, personality, and social cognition. Perspect. Psychol. Sci. 4:274-90
215. Miekisch W, Herbig J, Schubert JK. 2012. Data interpretation in breath biomarker research: pitfalls and directions. J. Breath Res. 6:036007
216. Amann A, Miekisch W, Pleil J, Risby T, Schubert W. 2010. Methodological issues of sample collection and analysis of exhaled breath. In Exhaled Biomarkers, Eur. Respir. Soc. Monogr. 49, ed. I Horvath, JC de Jongste, pp. 96-114. Lausanne: Eur. Respir. Soc.
217. Amann A, SmithD, eds. 2005. Breath Analysis for Clinical Diagnosis and Therapeutic Monitoring. Singapore: World Scientific Publishing
218. Marczin N, Yacoub M H, Kharitonov S, Barnes P, eds. 2002. Disease Markers in Exhaled Breath: Basic Mechanisms and Clinical Applications. New York: Marcel Dekker Inc.