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Medical Applications of Exhaled Breath Analysis and Testing

PCCSU Volume 25, Lesson 3

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

Hardware/software requirements: Web browsing device with working Web browser.

PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Alquam Mashir, Kelly Paschke; Daniel Laskowski. RT; and Raed A. Dweik, MBBS, FCCP

Ms. Mashir is Research Technologist, Cleveland Clinic; Ms. Paschke is Research Technician, Cleveland Clinic; Mr. Laskowski is Director of Advanced Physiology Core, Cleveland Clinic, Respiratory Institute and Department of Physiology; and Dr. Dweik is Associate Professor and Director, Cleveland Clinic Foundation, Cleveland, Ohio.

Ms. Mashir, Ms. Paschke, and Mr. Laskowski have disclosed no significant relationships with the companies/organizations whose products or services may be discussed within this chapter.

Dr. Dweik has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within this chapter:

Cleveland Clinic – university grant monies
National Institutes of Health, State of Ohio – grant monies

Objectives

  1. Identify the composition of exhaled breath.
  2. Determine the sources of volatile organic compounds in exhaled breath.
  3. Discuss breath tests in current clinical use.
  4. Evaluate the role of exhaled nitric oxide in asthma management.
  5. Appreciate the potential of exhaled breath analysis as a diagnostic tool.
  6. List advantages and disadvantages of breath analysis as a clinical tool.

Key words: aerosols; asthma; biomarkers; breath; breathprint; breath test; devices; exhaled breath; exhaled breath condensate; Food and Drug Administration; fraction of exhaled nitric oxide; gas chromatography; lung; lung cancer; mass spectrometry; nitric oxide; pulmonary; sensors; volatile organic compounds

Abbreviations: FDA = US Food and Drug Administration; Feno = fraction of exhaled nitric oxide; GC-MS = gas chromatography mass spectrometry; MS = mass spectrometry; NO = nitric oxide; ppb = parts per billion; VOC = volatile organic compound

Background

Similar to a fingerprint, every individual has a “breathprint” that can provide useful information about his or her state of health. This print comprises the thousands of molecules that are expelled with each breath we exhale. The history of studying breath as a medical test is as old as medicine itself. Hippocrates described fetor oris and fetor hepaticus in his treatise on breath aroma and disease,1 and clinicians have long noticed that patients with specific diseases, such as diabetes, liver disorders, and kidney failure, had distinct changes in the smell of their breath. Research in the past few years has uncovered the scientific and chemical basis for such clinical observations and with the help of modern mass spectrometry (MS) and gas chromatography mass spectrometry (GC-MS) instruments, we have been able to identify thousands of unique substances in exhaled breath.2 These substances include elemental gases, such as hydrogen, nitric oxide (NO), and carbon monoxide, and a vast array of volatile organic compounds (VOCs). Exhaled breath also carries aerosolized droplets that can be collected as exhaled breath condensate that contains endogenously produced nonvolatile compounds, such as dissolved proteins.3

Rationale for Using Exhaled Breath Testing

Most people recognize commonly used breath tests such as breathalyzers used by police to test drunk drivers. However, breath testing has far more sophisticated applications. Breath analysis is rapidly evolving as a new frontier in medical testing for disease states in the lung and beyond.1 Breath analysis is now used to diagnose and monitor asthma, check for transplant organ rejection, detect lung cancer, and test for Helicobacter pylori infection—and the list is growing.1,4 A major milestone in the scientific study of breath was marked 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—a lot more. Based on gas-liquid partition chromatography analysis, Pauling reported the presence of 250 substances in exhaled breath.5 We now have the technology to test for any and all of these components. The field of breath analysis has made considerable advances in the 21st century and the utility of breath analysis in health care is advancing quickly. The science is rapidly expanding, the technology is improving, and several new applications have been developed or are under commercial development.

Sources of Volatile Organic Compounds in Exhaled Breath

In addition to the traditional gases of oxygen, nitrogen, and carbon dioxide, exhaled breath contains several other elemental gases, including NO and carbon monoxide. Exhaled breath also contains gases and compounds that are produced locally in the lungs and airways (eg, NO), the GI tract, the sinuses, and/or the oral cavity. The major interest in exhaled breath analysis, however, originated from the fact that breath reflects metabolic reactions occurring within the body. The vast surface area of the lung allows compounds that are volatile at body temperature to escape the circulation when the blood passes through the lungs and enter into the alveolar space, eventually coming out in the exhaled breath. In a sense, alveolar gas represents a headspace for the entire circulation. Thus, at least in theory, any potentially volatile compound produced endogenously anywhere in the body can be present in exhaled breath as long as it enters the bloodstream. Interestingly, many of the compounds in exhaled breath are inhaled from the ambient environment and exhaled back out (modified or unmodified), reflecting environmental exposure.

Clinical Applications of Exhaled Breath Testing

A major breakthrough over the past decade has been the increase in breath-based tests approved by the US Food and Drug Administration (FDA). Devices measuring common breath gases (oxygen, nitrogen, water vapor, and CO2) in patient respiratory monitoring have served as a platform for technological growth in clinical breath-testing applications. A few exhaled breath tests have demonstrated clinical utility and are in widespread use, and several FDA-approved devices are available. These widely used exhaled breath tests include detection of blood alcohol concentration (Table 1) and exhaled CO2 (Table 2). Other clinical applications of exhaled breath analysis include testing for H pylori infection, lactose intolerance, heart transplant rejection, and, more recently, monitoring of airway inflammation by means of exhaled NO (Table 3).


Table 1Breath Analysis Devices Approved by the FDA for Breath Alcohol, in Chronological Order

Detected Molecule Disease/Condition Trade Name of Analysis Instrument Technique Manufacturer FDA Approval Date
Alcohol Alcohol intoxication AlcoMate CA 2000 Digital Alcohol Detector Semiconductor oxide sensor KHN Solutions LLC; San Francisco, CA August 11, 2004
Alcohol Alcohol intoxication Alcohawk Precision Digital Alcohol Detector Semiconductor oxide sensor Q3 Innovations, LLC; Eagan MN February 9, 2005
Alcohol Alcohol intoxication AL-5000 Breath Alcohol Tester Semiconductor oxide sensor Sentech Korea Corp; Goyang, South Korea October 30, 2006
Alcohol Alcohol intoxication Breath Alcohol Check .02 Detection System Electrochemical analyzer Akers Biosciences Inc; Thorofare, NJ December 18, 2006
Alcohol Breath alcohol Bactrack Breath Analyzer Semiconductor oxide sensor KHN Solutions LLC; San Francisco CA September 14, 2007
Alcohol Breath alcohol AlcoHAWK PT500 Fuel cell sensor Q3 Innovations, LLC; Independence, IA July 25, 2008
Alcohol Breath alcohol Bactrack Select Breathalyzer (models S30, S50, S70) Semiconductor (Si) oxide sensor KHN Solutions LLC; San Francisco, CA March 19, 2009
Alcohol Breath alcohol Bactrack Select Breathalyzer Model S80 Fuel cell sensor KHN Solutions LLC; San Francisco, CA March 24, 2009

Reflects manufacturer information at time of FDA approval. Information from the FDA’s Medical Devices Web page.30


Table 2Breath Analysis Devices Approved by the FDA for Exhaled Carbon Dioxide, in Chronological Order

Detected Molecule Disease/
Condition
Trade Name of Analysis Instrument Technique Manufacturer FDA Approval Date
CO2, O2, N2O Respiration Consolidated Nier model 21-201 Isotope Ratio Mass Spectrometer Dual inlet system gas isotope ratio MS Consolidated Electrodynamics Corporation, Inc; Pasadena, CA Before May 28, 1976
CO2 Respiration Tidal Wave Carbon Dioxide Monitor System, Model 610   Novametrix Medical Systems, Inc; Wallingford, CT November 20, 1996
13C18O2, O2, 15N2O Respiration ABCA-NT Gas Isotope Ratio Mass Spectrometer Continuous flow gas isotope ratio MS Europa Scientific Ltd; Concord, MA December 16, 1997
CO2, O2, N2O, anesthetic agents Respiration, ventilation Datex Ohmeda Compact Airway module M- CAiOVX and M- COVX Infrared and paramagnetic sensors Datex- Ohmeda, Inc; Tewksbury, MA August 23, 2000
13CO2/12CO2 H pylori UBiT-IR300 Spectrophotometer Infrared spectrometer Otsuka Pharmaceutical Co, Ltd; Tokyo, Japan December 21, 2001
O2, CO2, N2O, anesthetic agents Anesthetics, respiration BSM-4100A Infrared spectrometer Nihon Kohden America, Inc; Foothill Ranch, CA October 24, 2000
13CO2 H pylori BreathTek UBiT UBT Infrared spectrometer Meretek Diagnostics, Inc; Nashville, TN January 17, 2002
O2, CO2, N2O, anesthetic agents Anesthetics, respiration AG-920RA Sensor technology Nihon Kohden America, Inc; Foothill Ranch, CA July 25, 2002
O2,CO2, N2O, anesthetic agents Anesthetics, respiration BSM-5130A Series Bedside Monitor (anesthesia) Sensor technology Nihon Kohden America, Inc; Foothill Ranch, CA March 4, 2003
CO2 Respiration Datex-Ohmeda S/5 Single- Width Airway Module, M- MINIC Infrared and paramagnetic sensors GE Healthcare; Needham, MA April 23, 2003
13CO2 H pylori POCone Infrared Spectrophotometer Infrared spectrophotometer Otsuka Pharmaceutical Co Ltd; Tokyo, Japan July 15, 2004
13CO2 Ventilation C-CO2 Colorimetric CO2 Indicator Colorimetric Marquest Medical Products, Inc; Englewood, CO March 1, 2005
13CO2 Ventilation Datex-Ohmeda S/5 Single- Width Airway Module, E- MINIC Narrow band infrared sensor GE Healthcare; Needham, MA October 14, 2005
13CO2 Respiration OLG-2800A Sensor technology Nihon Kohden America, Inc; Foothill Ranch, CA December 27, 2006
CO2 Respiration
during anesthesia
EMMA Emergency Capnometer Infrared gas analysis Phasein AB; Danderyd, Sweden December 28, 2007
CO2 Ventilation status Nihon Kohden TG-970P Series CO2 Sensor Kit Infrared absorption spectrometry Nihon Kohden America, Inc; Foothill Ranch, CA March 2, 2009

Reflects manufacturer information at time of FDA approval. Information from the FDA’s Medical Devices Web page.30


Table 3Selected Breath Analysis Devices Approved by the FDA for Breath Testing, in Chronological Order

Detected Molecule Disease/Condition Trade Name of Analysis Instrument Technique Manufacturer FDA Approval Date
H2 Lactose malabsorption Micro H2 Electrochemical gas sensor Micro Direct, Inc; Auburn, ME January 24, 1997
NO Asthma, airway inflammation NIOX Chemiluminescenc e gas analyzer Aerocrine AB; Solna, Sweden April 30, 2003
Alkanes (C4-C20) and monomethylalkanes Grade 3 heart allograft rejection Heartsbreath GC-MS Menssana Research, Inc; Fort Lee, NJ February 24, 2004
H2 Lactose malabsorption Micro H2 Breath Monitoring Device with Hydra Software Utility Electrochemical gas sensor Micro Direct, Inc; Lewiston, ME May 19, 2004
Carbon monoxide Carbon monoxide poisoning and carboxyhemoglobin EC50 ToxCO + Electrochemical gas sensor technology Bedfont Scientific Ltd; Rochester, UK February 21, 2008
NO Asthma, airway inflammation NIOX MINO Electrochemical sensor Aerocrine AB; Solna, Sweden March 3, 2008

Reflects manufacturer information at time of FDA approval. Information from the FDA’s Medical Devices Web page.30


Exhaled NO for Asthma Diagnosis and Management
One recent landmark in clinical breath testing occurred in 2003 when the FDA approved the first device that measures the fraction of exhaled nitric oxide (Feno) for asthma monitoring (the term Feno is currently recommended by the American Thoracic Society for reporting exhaled NO levels6). Historically, NO has long been known as an atmospheric pollutant present in vehicle exhaust emissions and cigarette smoke, but the discovery that it is a biological mediator led to many breakthroughs in our understanding of human physiology and disease. NO is endogenously synthesized by one of three nitric oxide synthases, which convert l-arginine to l-citrulline and NO in the presence of oxygen and several cofactors. All three nitric oxide synthases (type I, II, and III) are widely expressed in various tissues, including the lungs.7,8 The advent of chemiluminescence analyzers in the early 1990s allowed the detection of low parts-per-billion (ppb) levels of NO in exhaled breath.9 The finding of high Feno in asthma was quickly followed by the observation that these levels decreased in response to treatment with corticosteroids.10,11 This quickly prompted the evaluation of exhaled NO as a potential noninvasive method to diagnose asthma and monitor the response to antiinflammatory therapy. Although several studies suggest a role for NO in asthma pathogenesis, the exact role of NO in asthma and airway reactivity has remained elusive and remains an area of active investigation. Whether NO is beneficial, through its bronchodilator and antioxidant effects, or harmful, by inducing inflammation, remains unclear.12,13 Despite these uncertainties, standardization of Feno measurement was followed by several large clinical and population studies demonstrating that Feno levels can be useful in the diagnosis of asthma14 and in monitoring disease activity/airway inflammation and response to therapy.11 More recently, it has been shown that subclassification by Feno may be useful in identifying the at-risk population for severe asthma. Asthmatics who have high Feno levels share several characteristics regardless of their asthma severity as it is currently defined. Asthmatics with high Feno are younger and received an asthma diagnosis at a younger age. They are atopic and have more eosinophilic airway inflammation, more airway reactivity, more airflow limitation, and more hyperinflation.15

Potential advantages for measuring exhaled NO in asthma patients include its noninvasive nature, ease of repeat measurements, and use in children and patients with severe airflow obstruction in whom other techniques would be difficult or impossible to perform.12 Exhaled NO may also be more sensitive than previously available tests in detecting airway inflammation.14 Several issues, however, had to be addressed before exhaled NO could become a useful clinical tool in routine asthma monitoring and management.16 First, researchers needed a better understanding of the role of NO in asthma pathogenesis. Second, the methods and equipment for measuring NO needed to be standardized. Third, large population studies were needed to determine the normal range of exhaled NO levels and the effect of confounding factors.12,16 Last but not least, interpretative strategies had to be devised and put in place for the different potential uses and applications. The observations that have been consistent in the literature, however, are that atopic individuals tend to have higher Feno while smokers tend to have lower Feno.17 A more difficult problem to address in the NO field has been the establishment of normal healthy population values for Feno. While several studies have tried to address the issue of normative values, they were done in different populations, addressed different potential confounders, and reported their results in different ways.17-20 Furthermore, “reference values” derived from a “normal” population may not be applicable in patients with asthma. This raises the question of whether normal values are at all useful when it comes to Feno monitoring in asthma. It is clear from reviewing the literature that the Feno value by itself is not sufficient; rather, it needs to be taken within the clinical context. Different studies have identified various possible confounders that affect Feno, including age, sex, weight, height, diurnal variation, and food intake, among others.

The most consistent confounders have been atopy (associated with higher Feno levels) and smoking (associated with lower Feno levels). Beyond the confounding variables of atopy and smoking, several issues need to be considered in order to interpret Feno levels in the appropriate context. Was the measurement obtained in someone who has symptoms or in an asymptomatic individual? Was it performed as a screening or to aid in diagnosis? Is the individual known to have asthma? And if so, is he/she receiving therapy? Does he/she have previous Feno levels on record and if so, how does this level compare? There is considerable overlap between the Feno levels in healthy individuals and asthmatics, so defining different cut points for different clinical settings may be more clinically useful than comparing with normative Feno values. Once the clinical setting is taken into consideration, certain patterns begin to emerge. Feno levels >45 to 50 ppb21 may predict steroid responsiveness while levels <35 ppb can suggest that optimal asthma control has been achieved in an asthmatic patient receiving therapy.22 Feno levels >20 to 25 ppb suggest the presence of asthma in a steroid-naive individual with symptoms, while lower levels are not likely to be associated with airway inflammation.14,23,24

Recent Advances in Breath Analysis

Lung Cancer Screening
The number of deaths from lung cancer each year surpasses those of the next four most common causes of cancer-related mortality combined (colon, breast, pancreas, prostate).1 One of the reasons for this is the fact that lung cancer is usually diagnosed late in its course and screening methods for early detection of lung cancer are desperately needed. Differences in the cellular processes of lung cancer cells can result in breath volatiles unique to lung cancer, allowing breath analysis to be used as a test for lung cancer. Two very different approaches have been used in lung cancer diagnosis by exhaled breath analysis. The first approach uses MS devices to find and identify the individual volatiles that are unique in the breath of lung cancer patients. The second uses sensor array (electronic nose) devices to see if unique patterns of output can be identified. The composite output of the array represents a pattern of changes based on the pattern of chemicals that the sensors have been exposed to. The specific volatiles and their concentrations are not identified by these sensors; rather, a pattern of changes based on the entire mixture of volatiles present in the sample is identified. The electronic nose description of these sensor arrays relies on their similarity to the human nose, which can recognize the smell of an orange, for example, without the ability to identify the chemical components that result in such a unique smell. Like a human nose, the electronic nose also requires prior exposure (training) to a particular smell (pattern) in order to recognize it. While there has been some overlap in the models developed from MS studies, a consistent set of unique volatiles has not been produced. The results from MS studies have been quite promising but have not yet reached a level of accuracy that would permit a clinical application, and this modality has not been tested on large and diverse enough groups to be proven consistent. Studies using the electronic nose-type devices reported a sensitivity of 71% and specificity of 92%, for an overall accuracy of 85%.25,26 The advantages of these devices are that they are relatively inexpensive and easier to use as a point-of-care test than the MS technologies that have been studied. But in order to be useful as an up-front screening test of high-risk populations, as a tool to evaluate pulmonary nodules, or as a diagnostic test for lung cancer, a breath test should be at least 90% to 95% sensitive and specific.6 Thus, there remains a great need for accurate, inexpensive, noninvasive testing in the field of lung cancer. Breath testing to analyze patterns of volatile organic compounds in the exhaled breath has shown some promise towards meeting this need. We hope that progress will continue in this area so that a clinically useful breath test can be developed. This process may serve as a model for breath test development for other diseases.

Specific Breath Biomarkers That Have Been Associated With Disease
Nearly all the VOCs of interest as biomarkers have concentrations in the nanomolar or picomolar range. To detect this range, highly sensitive devices and precise analytical techniques are needed. Some VOCs that have been identified in exhaled breath include alkanes, such as methane, the simplest hydrocarbon, which can be present in high levels in patients with irritable bowel syndrome, oxidative stress, and acute myocardial infarction. Concentrations of ethane, pentane, and larger alkanes have been reported to be elevated in breast cancer, lung cancer, heart allograft rejection, and lipid peroxidation.4,27 Monomethylated alkanes, such as dimethylcyclohexane, methylheptane, methylcyclododecane, and tetramethylbenzene, have been identified in pulmonary tuberculosis.4,27,28 High concentrations of amines have been identified in renal failure.4 Sulfides in the breath have been reported in various liver diseases and periodontal conditions.4 Aldehydes, such as formaldehyde and acetaldehyde, are found to be uniquely high in prostate cancer.4

Exhaled Breath Condensate
Exhaled breath condensate is a potentially rich source for nonvolatile biomarkers that can provide valuable information about respiratory and systemic diseases. Aerosolized droplets in exhaled breath can be captured by a variety of methods and analyzed for a wide range of biomarkers, from metabolic end products and proteins to a variety of cytokines and chemokines, and the possibilities continue to expand.29 This technique remains largely a research tool at this point. A major hurdle delaying the transition of exhaled breath condensate from the laboratory to clinical testing has been the standardization of sample collection methods.3,29

The Promises and Limitations of Exhaled Breath Analysis as a Clinical Tool

Advantages of breath testing include its noninvasive and nonintrusive nature and that it can be performed repeatedly without limits to amount (unlike blood), timing (unlike urine), or frequency (unlike chest radiography) and has no age limits (neonates to the elderly). Breath testing has the potential to be inexpensive and portable, lending itself to a wide range of settings, from the hospital to the clinic, the home, and even remote areas and developing countries. Breath testing offers the possibility of providing real-time results in point-of-care or at-home testing, and it increases the potential for personalized medicine. Disadvantages of breath testing include the multitude of possible confounders, from host variations to diet and the environment. Lack of standardization is a major problem as well; frequency of sampling (and timing it to the respiratory cycle) and the need to control flow, pressure, and ambient conditions are key issues. Historically, physician acceptance of this nontraditional method of testing has been a major hurdle, too.

Summary

Breath chemistry is complex and breath analysis can provide information on different disease states. Exhaled NO levels are high in asthma and their measurement may be useful in diagnosis and monitoring. Exhaled breath analysis by MS or the electronic nose can detect lung cancer in humans with a reasonable degree of accuracy. While there are currently several FDA-approved tests and devices for breath analysis, evolving technologies in sampling, sensor design, standardization, and analytical methods have the potential to provide many more tests that can transform medicine on the personal level and on a global scale.


References

  1. Dweik RA, Amann A. Exhaled breath analysis: the new frontier in medical testing [editorial]. J Breath Res. 2008;2(3):1-3. doi:10.1088/1752-7155/2/3/030301.
  2. Phillips M, Herrera J, Krishnan S, Zain M, Greenberg J, Cataneo RN. Variation in volatile organic compounds in the breath of normal humans. J Chromatogr B Biomed Sci Appl. 1999;729(1-2):75-88.
  3. Grob NM, Aytekin M, Dweik RA. Biomarkers in exhaled breath condensate: a review of collection, processing and analysis. J Breath Res. 2008;2(3):037004. doi: 10.1088/1752-7155/2/3/037004
  4. Mashir A, Dweik RA. Exhaled breath analysis: the new interface between medicine and engineering. Adv Powder Technol. 2009;20(5):420-425.
  5. Pauling L, Robinson AB, Teranishi R, Cary P. Quantitative analysis of urine vapor and breath by gas-liquid partition chromatography. Proc Natl Acad Sci U S A. 1971;68(1):2374-2376.
  6. 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 Care Med. 2005;171(8):912-930.
  7. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A. 1987;84(24):9265-9269.
  8. Dweik RA, Erzurum SC. Regulation of nitric oxide (NO) synthases and gas phase NO by oxygen. In: Marczin N, Kharitonov SA, Yacoub MH, Barnes PJ, eds. Disease Markers in Exhaled Breath. New York, NY: Marcel Dekker, Inc; 2003:235-246. Lung Biology in Health and Disease.
  9. Gustafsson LE, Leone AM, Persson MG, Wiklund NP, Moncada S. Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun. 1991;181(2):852-857.
  10. Kharitonov SA, Yates D, Robbins RA, Logan-Sinclair R, Shinebourne EA, Barnes PJ. Increased nitric oxide in exhaled air of asthmatic patients. Lancet. 1994;343(8890):133-135.
  11. Silkoff PE, McClean P, Spino M, Erlich L, Slutsky AS, Zamel N. Dose-response relationship and reproducibility of the fall in exhaled nitric oxide after inhaled beclomethasone dipropionate therapy in asthma patients. Chest. 2001;119(5):1322-1328.
  12. Özkan M, Dweik RA. Nitric oxide and airway reactivity. Clin Pulm Med. 2001;8(4):199-206.
  13. Dweik RA, Comhair SA, Gaston B, et al. NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response. Proc Natl Acad Sci U S A. 2001;98(5):2622-2627.
  14. Smith AD, Cowan JO, Filsell S, et al. Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests. Am J Respir Crit Care Med. 2004;169(4):473-478.
  15. Dweik RA, Sorkness RL, Wenzel S, et al. Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit Care Med. 2010;181(10):1033-1041.
  16. Dweik RA. The promise and reality of nitric oxide in the diagnosis and treatment of lung disease. Cleve Clin J Med. 2001;68(6):486, 488, 490, 493
  17. Olin AC, Bake B, Torén K. Fraction of exhaled nitric oxide at 50 mL/s: reference values for adult lifelong never-smokers. Chest. 2007;131(6):1852-1856.
  18. Olivieri M, Talamini G, Corradi M, et al. Reference values for exhaled nitric oxide (reveno) study. Respir Res. 2006;7:94.
  19. Buchvald F, Baraldi E, Carraro S, et al. Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years. J Allergy Clin Immunol. 2005;115(6):1130-1136.
  20. Travers J, Marsh S, Aldington S, et al. Reference ranges for exhaled nitric oxide derived from a random community survey of adults. Am J Respir Crit Care Med. 2007;176(3):238-242.
  21. Smith AD, Cowan JO, Brassett KP, et al. Exhaled nitric oxide: a predictor of steroid response. Am J Respir Crit Care Med. 2005;172(4):453-459.
  22. Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med. 2005;352(21):2163-2173.
  23. Berry MA, Shaw DE, Green RH, Brightling CE, Wardlaw AJ, Pavord ID. The use of exhaled nitric oxide concentration to identify eosinophilic airway inflammation: an observational study in adults with asthma. Clin Exp Allergy. 2005;35(9):1175-1179.
  24. Dupont LJ, Demedts MG, Verleden GM. Prospective evaluation of the validity of exhaled nitric oxide for the diagnosis of asthma. Chest. 2003;123(3):751-756.
  25. Machado RF, Laskowski D, Deffenderfer O, et al. Detection of lung cancer by sensor array analyses of exhaled breath. Am J Respir Crit Care Med. 2005;171(11):1286-1291.
  26. Mazzone P, Hammel J, Dweik R, et al. Diagnosis of lung cancer by the analysis of exhaled breath with a colorimetric sensor array. Thorax. 2007;62(7):565-568.
  27. Buszewski B, Kesy M, Ligor T, Amann A. Human exhaled air analytics: biomarkers of diseases. Biomed Chromatogr. 2007;21(6):553-566.
  28. Phillips M, Basa-Dalay V, Bothamley G, et al. Breath biomarkers of active pulmonary tuberculosis. Tuberculosis (Edinb). 2010;90(2):145-151.
  29. Horvath I, Hunt J, Barnes PJ, et al. Exhaled breath condensate: methodological recommendations and unresolved questions. Eur Respir J. 2005;26(3):523-548.
  30. U.S. Food and Drug Administration. Medical devices. http://www.fda.gov/MedicalDevices/default.htm. Accessed January 24, 2011.