PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Adv Powder Technol. Author manuscript; available in PMC 2010 October 12.
Published in final edited form as:
Adv Powder Technol. 2009 September; 20(5): 420–425.
PMCID: PMC2952965
NIHMSID: NIHMS202261

Exhaled breath analysis: The new interface between medicine and engineering

Abstract

Exhaled breath testing is becoming an increasingly important non-invasive diagnostic method that can be used in the evaluation of health and disease states in the lung and beyond. Potential advantages of breath tests over other conventional medical tests include their non-invasive nature, low cost, and safety. To advance in this area further, however, there has to be a close collaboration between technical experts and engineers who have devices looking for clinical application(s), the medical experts who have the clinical problems looking for a test/biomarker that can be helpful in diagnosis or monitoring, and industry/commercial experts who can build and commercialize the final product.

Keywords: Exhaled breath, Volatile organic compounds, Medicine, Engineering

As we breathe out we expel thousands of molecules into the air. When correctly captured and analyzed these molecules make a “breath-print” that can tell a lot about the state of our health [1]. The synergies between medicine and engineering in this area have the potential to revolutionize the way we monitor health and disease and allow us to provide personalized care for each individual based on his or her own “breath-print” [1].

The current conditions in the breath analysis field could not be better: the science is mature, the technology is exploding, industry is interested, and the medical community is embracing this noninvasive method of testing. Thanks to major engineering and breakthroughs in the 20th century including new technologies (infrared, electrochemical, chemiluminescence, and others) and the development of very sensitive modern mass spectrometry (MS), gas chromatography (GC) and gas chromatography mass spectrometry (GC–MS) instruments, we can now identify thousands of unique substances in exhaled breath. These substances include elemental gases like nitric oxide and carbon monoxide and a multitude of volatile organic compounds (Table 1). Furthermore, exhaled breath also carries aerosolized droplets collected as “exhaled breath condensate” that have non-volatile compounds that can be captured by a variety of methods and analyzed for a wide range of biomarkers from metabolic end products to proteins to a variety of cytokines and chemokines and the possibilities continue to expand [2,3]. With various technologies available to test for any and all of these exhaled breath components (Table 2), several methods are now in clinical use or about ready to enter that arena. Breath analysis is now used to diagnose and monitor asthma, to check for transplant organ rejection, and to detect lung cancer, to mention a few applications. Thus, the 21st century promises to deliver a revolution in our understanding of the constituents of exhaled breath and the advancement of the field of breath analysis and testing.

Table 1
Markers identified in exhaled breath with their chemical structure, the associated medical conditions, and the techniques used to measure them.
Table 2
Techniques and devices used in breath analysis.

While the concept of using breath analysis as a medical test may be a surprise to engineering professionals, it is an easier to accept fact for medical professionals. The history of medicine is replete with discoveries that led to our current day understanding of the diagnostic potential of exhaled breath. Hippocrates described fetor oris and fetor hepaticus in his treatise on breath aroma and disease, Lavoisier and Laplace in 1784 showed that respiration consumes oxygen and eliminates carbon dioxide [4], Nebelthau in mid 1800s showed that diabetics emit breath acetone [5], and Anstie in 1874 isolated ethanol from breath (which is the basis of breath alcohol testing today) [6]. A major breakthrough in the scientific study of breath started in the 1970s when Linus Pauling demonstrated that there is more to exhaled breath than the classic gases of nitrogen, oxygen, carbon dioxide and water vapor. Using gas–liquid partition chromatography analysis, Pauling demonstrated the presence of 250 substances in exhaled breath [7].

The upward trajectory of the breath analysis field and related product development and manufacturing was very clear after a three-day Breath Analysis Summit hosted at the Cleveland Clinic in November 2007. The Summit was perhaps a turning point in the field as it attracted participants from 22 countries and 18 states [1]. The Summit brought together industry executives and entrepreneurs with scientists, engineers, and clinicians to discuss key trends, future directions, and upcoming technologies in breath analysis and medicine. The major focus of the Summit was on new technologies and medical applications and to address the major hurdles that faced this field as it transitions from the laboratory to clinical testing. Topics included exhaled nitric oxide, exhaled breath condensate, electronic nose and sensor arrays, mass spectrometry and bench top instrumentation, and cutting edge sensor technologies. Medical applications that were covered included asthma, COPD, pulmonary hypertension, other respiratory diseases, gastrointestinal diseases, occupational diseases, critical illness, and cancer [1]. The major conclusions of the summit were clear. Multidisciplinary collaboration is the only way to keep moving the field forward and to allow breath analysis and testing to achieve their potential and hold their rightful place among other accepted medical tests. The members of this team need to include scientist and engineers who have the technical knowledge and can build the appropriate devices, medical professionals who understand the disease processes and know the areas of greatest medical need, as well as industry to build devices for testing and later distribute the successful ones to a national and worldwide healthcare market. This is where the synergy between medicine and engineering is at its best.

Most likely to succeed in these endeavors are integrated multidisciplinary teams that join colleagues in industry and academia for the focused purpose of rapid development and commercialization of urgently needed non-invasive devices that will guide the diagnosis and monitoring of different diseases by exhaled breath testing. While each of these team members can independently make major contributions to their respective fields, the potential for having them work together is enormous and cannot be overstated. The process could start with a clinical need as identified by a physician; the appropriate sensor(s) can then be developed by team members with biochemical and engineering expertise. It is not uncommon, however, for the process to start from the engineering end when a new technology or device is found to be particularly sensitive or specific to detect a certain molecule or group of molecules and the medical team is approached for a possible medical application of this new technology. Regardless of where the process starts, however, it is likely to need continuous work and refinement from all involved. Once a sensor is developed a prototype is built and validated by an industrial partner and sent to the medical team for human testing. Depending on the human test results, the device may be sent back for further refinement and retesting. This process/cycle is repeated until a sensor/device achieves its expected goals. Once a device is ready, it goes back to the industry partner(s) for production on larger scale for clinical trials that will be needed for regulatory approval.

One great example of how the collaboration between technical, medical, and commercial professionals has resulted in a clinically useful tool is the measurement of exhaled nitric oxide (NO) in exhaled breath for monitoring airway inflammation. The advent of chemiluminescence analyzers in the early 1990s allowed the detection of low (ppb) levels of NO in exhaled breath [8]. This was quickly followed by the observation that patients with asthma had higher than normal levels of NO in their exhaled breath that was later linked to eosinophilic airway inflammation [9,10]. Standardization of the gas collection methods and measurement techniques allowed the industry to build the next generation of analyzers suitable for use in the clinical setting [11-14]. In 2003 the FDA approved the first desktop NO analyzer for monitoring airway inflammation in asthma [15]. This new test has evolved into an important tool in the modern management of asthma and airway inflammation. The use of exhaled NO in monitoring asthma is useful for several reasons. It is non-invasive, it can be performed repeatedly, and it can be used in children and patients with severe airflow obstruction where other techniques are difficult or not possible to perform. Exhaled NO may also be more sensitive than currently available tests in detecting airway inflammation which may allow more optimum therapy [13,16-22].

As breath analysis offers a window on lung physiology and disease, exhaled breath testing is becoming an increasingly important non-invasive diagnostic method that can be used in the evaluation of health and disease states in the lung and beyond. Potential advantages of breath tests over other conventional medical tests include their non-invasive nature, low cost, and safety. This is an area where the modern day advances in technology and engineering meet the ever expanding need in medicine for more sensitive, specific and non-invasive tests which makes this area a major front in the interface between medicine and engineering.

References

1. Dweik RA, Amann A. J Breath Res. 2008:030301. [PMC free article] [PubMed]
2. Horvath I, Hunt J, Barnes PJ, Alving K, Antczak A, Baraldi E, Becher G, van Beurden WJ, Corradi M, Dekhuijzen R, Dweik RA, Dwyer T, Effros R, Erzurum S, Gaston B, Gessner C, Greening A, Ho LP, Hohlfeld J, Jobsis Q, Laskowski D, Loukides S, Marlin D, Montuschi P, Olin AC, Redington AE, Reinhold P, van Rensen EL, Rubinstein I, Silkoff P, Toren K, Vass G, Vogelberg C, Wirtz H. Eur Respir J. 2005;26:523–548. [PubMed]
3. Grob NM, Aytekin M, Dweik RA. J Breath Res. 2008:037004. [PMC free article] [PubMed]
4. Duveen DI, Klickstein HS. Bull Hist Med. 1955;29:164–179. [PubMed]
5. Hubbard RS. J Biol Chem. 1920;43:57–65.
6. Baldwin AD. Am J Public Health. 1977;67:679–681. [PubMed]
7. Pauling L, Robinson AB, Teranishi R, Cary P. Proc Natl Acad Sci USA. 1971;68:2374–2376. [PubMed]
8. Gustafsson LE, Leone AM, Persson MG, Wiklund NP, Moncada S. Biochem Biophys Res Commun. 1991;181:852–857. [PubMed]
9. Kharitonov SA, Yates D, Robbins RA, Logan-Sinclair R, Shinebourne EA, Barnes PJ. Lancet. 1994;343:133–135. [PubMed]
10. Persson MG, Zetterstrom O, Agrenius V, Ihre E, Gustafsson LE. Lancet. 1994;343:146–147. [PubMed]
11. Am J Respir Crit Care Med. 1999;160:2104–2117. [PubMed]
12. Am J Respir Crit Care Med. 2005;171:912–930. [PubMed]
13. Grob NM, Dweik RA. Chest. 2008;133:837–839. [PubMed]
14. Grob NM, Dweik RA. J Breath Res. 2008:037002. [PMC free article] [PubMed]
15. Gill M, Graff GR, Adler AJ, Dweik RA. J Asthma. 2006;43:731–734. [PubMed]
16. Dweik RA. Cleve Clin J Med. 2001;68:486, 488, 490, 493. [PubMed]
17. Dweik RA, Comhair SA, Gaston B, Thunnissen FB, Farver C, Thomassen MJ, Kavuru M, Hammel J, Abu-Soud HM, Erzurum SC. Proc Natl Acad Sci USA. 2001;98:2622–2627. [PubMed]
18. Guo FH, Comhair SA, Zheng S, Dweik RA, Eissa NT, Thomassen MJ, Calhoun W, Erzurum SC. J Immunol. 2000;164:5970–5980. [PubMed]
19. Khatri SB, Ozkan M, McCarthy K, Laskowski D, Hammel J, Dweik RA, Erzurum SC. Am J Respir Crit Care Med. 2001;164:1844–1848. [PubMed]
20. Khatri SB, Hammel J, Kavuru MS, Erzurum SC, Dweik RA. J Appl Physiol. 2003;95:436–440. Discussion 435. [PubMed]
21. Dweik RA. Disease Markers in Exhaled Breath: Basic Mechanisms and Clinical Applications. In: Marczin N, Yacoub MH, editors. NATO Science Series. IOS Press; Amsterdam, Netherlands: 2002. pp. 159–166.
22. Ozkan M, Dweik RA. Clin Pulmonary Med. 2001;8:199–206.
23. Buszewski B, Kesy M, Ligor T, Amann A. Biomed Chromatogr. 2007;21:553–566. [PubMed]
24. Barker M, Hengst M, Schmid J, Buers HJ, Mittermaier B, Klemp D, Koppmann R. Eur Respir J. 2006;27:929–936. [PubMed]
25. Miekisch W, Schubert JK, Noeldge-Schomburg GF. Clin Chim Acta. 2004;347:25–39. [PubMed]
26. Phillips M, Cataneo RN, Ditkoff BA, Fisher P, Greenberg J, Gunawardena R, Kwon CS, Rahbari-Oskoui F, Wong C. Breast J. 2003;9:184–191. [PubMed]
27. Kneepkens CM, Lepage G, Roy CC. Free Radic Biol Med. 1994;17:127–160. [PubMed]
28. Mendis S, Sobotka PA, Euler DE. Free Radic Res. 1995;23:117–122. [PubMed]
29. Scholpp J, Schubert JK, Miekisch W, Noeldge-Schomburg GFE. J Neurotrauma. 2004;21:667–677. [PubMed]
30. Larstad MA, Toren K, Bake B, Olin AC. Acta Physiol (Oxf) 2007;189:87–98. [PubMed]
31. Aghdassi E, Allard JP. Free Radic Biol Med. 2000;28:880–886. [PubMed]
32. Mohler ER, 3rd, Reaven P, Stegner JE, Fineberg NS, Hathaway DR. J Chromatogr B Biomed Appl. 1996;685:201–209. [PubMed]
33. Skeldon KD, McMillan LC, Wyse CA, Monk SD, Gibson G, Patterson C, France T, Longbottom C, Padgett MJ. Respir Med. 2006;100:300–306. [PubMed]
34. Manolis A. Clin Chem. 1983;29:5–15. [PubMed]
35. Cope KA, Watson MT, Foster WM, Sehnert SS, Risby TH. J Appl Physiol. 2004;96:1371–1379. [PubMed]
36. Poli D, Carbognani P, Corradi M, Goldoni M, Acampa O, Balbi B, Bianchi L, Rusca M, Mutti A. Respir Res. 2005;6:71. [PMC free article] [PubMed]
37. Droz PO, Guillemin MP. J Occup Med. 1986;28:593–602. [PubMed]
38. Ross BM. BMC Res Notes. 2008;1:41. [PMC free article] [PubMed]
39. Phillips M, Cataneo RN, Condos R, Ring Erickson GA, Greenberg J, La Bombardi V, Munawar MI, Tietje O. Tuberculosis (Edinb) 2007;87:44–52. [PubMed]
40. Michael P. J Chromatogr B. 1999;729:75–88. [PubMed]
41. Sanchez JM, Sacks RD. Anal Chem. 2006;78:3046–3054. [PubMed]
42. Qin T, Xu X, Polak T, Pacakova V, Stulik K, Jech L. Talanta. 1997;44:1683–1690. [PubMed]
43. Reimann I, Mergemeier S, Ebner I, Scholz F. Fresen J Anal Chem. 1995;353:206–210. [PubMed]
44. Belda-Iniesta C, de Castro Carpeno J, Carrasco JA, Moreno V, Casado Saenz E, Feliu J, Sereno M, Garcia Rio F, Barriuso J, Gonzalez Baron M. Clin Transl Oncol. 2007;9:364–368. [PubMed]
45. van den Velde S, Quirynen M, van Hee P, van Steenberghe D. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;853:54–61. [PubMed]
46. Mitsubayashi K, Matsunaga H, Nishio G, Toda S, Nakanishi Y. Biosens Bioelectron. 2005;20:1573–1579. [PubMed]
47. Van den Velde S, Nevens F, Van Hee P, van Steenberghe D, Quirynen M. J Chromatogr B Analyt Technol Biomed Life Sci. 2008;875:344–348. [PubMed]
48. Phillips M, Cataneo RN, Ditkoff BA, Fisher P, Greenberg J, Gunawardena R, Kwon CS, Tietje O, Wong C. Breast Cancer Res Treat. 2006;99:19–21. [PubMed]
49. Manne J, Sukhorukov O, Jager W, Tulip J. Appl Opt. 2006;45:9230–9237. [PubMed]
50. Rolla G, Bruno M, Bommarito L, Heffler E, Ferrero N, Petrarulo M, Bagnis C, Bugiani M, Guida G. Eur J Clin Invest. 2008;38:728–733. [PubMed]
51. Thorpe MJ, Balslev-Clausen D, Kirchner MS, Ye J. Opt Express. 2008;16:2387–2397. [PubMed]
52. Cao W, Duan Y. Clin Chem. 2006;52:800–811. [PubMed]
53. Roberge MT, Finley JW, Lukaski HC, Borgerding AJ. J Chromatogr A. 2004;1027:19–23. [PubMed]
54. Ledochowski M, Widner B, Murr C, Sperner-Unterweger B, Fuchs D. Scand J Gastroenterol. 2001;36:367–371. [PubMed]
55. Minocha A, Mokshagundam S, Gallo SH, Rahal PS. Am J Gastroenterol. 1994;89:1797–1800. [PubMed]
56. Minocha A, Siddiqi S, Rahal PS, Vogel RL. Dig Dis Sci. 1994;39:1613–1617. [PubMed]
57. Babusikova E, Jesenak M, Durdik P, Dobrota D, Banovcin P. J Physiol Pharmacol. 2008;59(Suppl 6):9–17. [PubMed]
58. Scherer JJ, Paul JB, O’Keefe A, Saykally RJ. Chem Rev. 1997;97:25–52. [PubMed]
59. Wyse CA, Preston T, Yam PS, Sutton DG, Christley RM, Hotchkiss JW, Mills CA, Glidle A, Cumming DR, Cooper JM, Love S. Vet Rec. 2004;154:353–360. [PubMed]
60. Sandrini A, Johnson AR, Thomas PS, Yates DH. Respirology. 2006;11:325–329. [PubMed]
61. M.M.R.a.P. HERING. Mid-Infrared Coherent Sources and Applications. 2008:535–555.
62. Pleil JD, Lindstrom AB. Clin Chem. 1997;43:723–730. [PubMed]
63. Levitt MD, Furne JK, Kuskowski M, Ruddy J. Clin Gastroenterol Hepatol. 2006;4:123–129. [PubMed]
64. Christl SU, Murgatroyd PR, Gibson GR, Cummings JH. Gastroenterology. 1992;102:1269–1277. [PubMed]
65. Chatterjee S, Park S, Low K, Kong Y, Pimentel M. Am J Gastroenterol. 2007;102:837–841. [PubMed]