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* From National Heart & Lung Institute, Imperial College, Royal Brompton Hospital, London, UK.
Correspondence to: Sergei A. Kharitonov, MD, PhD, Section of Airway Disease, National Heart & Lung Institute, Imperial College, Dovehouse St, London SW3 6LY, UK; e-mail: s.kharitonov{at}imperial.ac.uk
Abstract
Assessing airway and lung inflammation is important for investigating the underlying mechanisms of asthma and COPD. Yet these cannot be measured directly in clinical research and practice because of the difficulties in monitoring inflammation. Noninvasive monitoring may assist in early recognition of asthma and COPD, assessment of its severity, and response to treatment, especially during disease exacerbations. There is increasing evidence that breath analysis may have an important place in clinical management of asthma and COPD. The article reviews the role of current noninvasive measurements of exhaled gases, such as nitric oxide (NO), inflammatory markers in exhaled breath condensate (EBC), and exhaled breath temperature, as well as novel methods in monitoring and management of asthma and COPD.
Key Words: asthma • COPD • exhaled breath condensate • exhaled nitric oxide
Biomarkers are objectively measured and evaluated indicators of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Measuring biomarkers in the breath is a very attractive approach to monitoring asthma1 and COPD inflammation because it is noninvasive and makes repeated sampling possible.23 However, there are important issues about reproducibility, variability, and sensitivity that need to be addressed before this approach can be recommended as an outcome measurement. There is relatively little information about how any of these biomarkers relate to other clinical outcomes, such as progression of the disease, severity of disease, clinical subtypes, or response to therapy. In the future, new assays may be useful in predicting disease progression, indicating disease instability, and in predicting response to current therapies and novel therapies, many of which are now in development.
Exhaled Nitric Oxide
Fractional exhaled nitric oxide (FENO) has been extensively investigated in asthma and has been shown to correlate with predominantly eosinophilic airway inflammation and to be reduced by corticosteroid therapy. There are European Respiratory Society and American Thoracic Society recommendations for measuring FENO.4 The measurement is highly reproducible in normal and asthmatic subjects if careful attention is paid to technique.5
Until recently, no day-to-day and home FENO monitoring was possible, as portable and simple nitric oxide (NO) analyzers were not available. The arrival of handheld portable NO analyzers that allows FENO measurements with sufficient accuracy and reproducibility may considerably change current management of asthma, as FENO can be measured on a daily basis by patients at home and frequently during their regular visits to their general practitioner.6
Asthma
Diagnosis:
Elevation of FENO, an airway-specific marker of predominantly eosinophilic inflammation, is not unique for asthma but may be used with > 90% specificity for the diagnosis of asthma in both adults7 and children.8 Considering the simplicity of the measurements especially with portable NO analyzers, FENO can be used cost effectively for screening of large populations. However, lower levels of NO in patients treated with inhaled corticosteroids (ICS) should be taken into consideration, as this may reduce the sensitivity of NO as a diagnostic tool. In contrary, normal FENO levels may differentiate patients with chronic nonasthmatic cough.
Monitoring of Airway Inflammation:
Symptoms of atopic asthma often begin in early childhood and mostly improve or even seem to disappear at puberty, but will relapse later in life. This persistent but latent airway inflammation, known as airway remodeling, leads to the thickening of the airway wall and may account for bronchial hyperresponsiveness, which could have a substantial impact on the progression of asthma. Elevated exhaled NO, blood eosinophil cell counts, and bronchial response to adenosine-5'-monophosphate correlated significantly with the quantity of tissue eosinophils in the bronchoscopy samples from adolescents in clinical remission of atopic asthma. This signifies that airway inflammation and remodeling are both ongoing processes even in subjects in clinical remission, and may be detected and monitored by routine exhaled NO measurements in clinic. It can be speculated that subjects with subclinical airway inflammation9 and elevated exhaled NO levels could benefit from an "early" antiinflammatory treatment, preventing subsequent airway remodeling and progression of asthma.
Management:
When measured longitudinally, the changes in FENO correlated significantly not only with changes in sputum eosinophils and hyperresponsiveness but also with lung function and asthma symptoms.110 An advantage of FENO as an easy-to-implement "loss-of-control-marker" is that increase in FENO precedes the fall in peak expiratory flow and asthma symptoms. Monitoring of asthma may be much more conclusive when repetitive FENO measurements instead of single assessment were used; changes in FENO correlate significantly not only with changes in sputum eosinophils and hyperresponsiveness but also with lung function and asthma symptoms. As portable exhaled NO analyzers are available, it is likely that this measurement will become routine in monitoring asthma in general practice and eventually by patients at home.
Treatment:
FENO behaves as a "rapid response" marker that is sensitive to steroid treatment because it may be significantly and dose-dependently reduced 6 h after a single dose of nebulized budesonide,11 or within 2 to 3 days12 after regular treatment with ICS. Noncompliance or cessation of treatment with ICS will return NO levels rapidly (3 to 5 days) to the pretreatment level12; with use of FENO measurements, maintenance doses of ICS may be significantly reduced without compromising asthma control.13
Combination inhalers (ICS plus long-acting ß-agonists) are the first-line treatment in asthma, although not in the United States. It is important, however, to monitor the underlying airway inflammation, independently of patients’ lung function and symptoms, which are affected by long-acting ß-agonists. Symptom-driven dosing with combination inhalers may be useful in the future, as long as the dose of the steroid can be determined by the degree of symptoms at a particular time. We suggest that serial FENO measurements using a portable NO analyzer may be used to adjust doses of combination therapy based on control of inflammation in asthma.
COPD
Conventionally measured FENO in COPD is less useful, as the levels are usually normal or only slightly elevated, except during exacerbations.2 Recently the measurement of FENO has been extended by making measurements of exhaled NO at different flows (multiple exhalation flow technique [MEFT]), so that it is possible to partition airway-derived NO that is flow independent and peripheral NO (CALV) derived from alveoli and probably small airways. Using this technique, it is possible to show that while airway NO is low or normal in COPD, there is an increase in CALV that is related to disease severity and affected by neither smoking nor conventional ICS.14 This may reflect the increase in inducible NO synthase (iNOS) in the lung periphery of patients with COPD. This CALV may prove to be a useful noninvasive biomarker of COPD inflammation.
Clinical Areas for Use of Exhaled NO in COPD
Early Detection of Onset of Exacerbations:
The patient’s failure to report exacerbations, which is mostly based on their symptoms and color of sputum, significantly increases the risk of subsequent emergency hospitalization and is associated with a slower recovery. NO is increased in exhaled breath from very early stages of the common cold,1516 which often triggers exacerbation in COPD. Potentially, portable NO analyzers may be used by the patients at home to alert them, in addition to symptoms, so that prompt treatment improves exacerbation recovery (Fig 1
). Further studies using different technologies, for example, portable mass spectrometry/spectroscopy, to analyze exhaled breath using pattern recognition software are clearly needed, however, to differentiate viral from bacterial infection in order to initiate an early and appropriate treatment.
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Monitoring of Small Airway Inflammation in COPD:
Alveolar (CALV) exhaled NO can be reproducibly measured using the MEFT, is increased in COPD, reflects peripheral airway inflammation, and is related to disease severity. MEFT FENO measurements are highly reproducible, free of diurnal variation, unaffected by smoking, bronchodilator, or ICS,14 and therefore can be used for COPD monitoring.
COPD Severity and Progression:
Severity-related increase of the CALV may be due to higher presence of iNOS-positive cells in alveolar walls in patients with more severe COPD but not with severe emphysema that shows a lower percentage of iNOS-positive alveolar macrophages than in patients with milder disease.17 Patient with the Global Initiative for Chronic Obstructive Lung Disease stage II have CALV levels14 similar to those of patients with more severe asthma, suggesting similar pathophysiologic mechanisms and/or similar extent of airway/lung inflammation that may be corrected by similar treatment.
NO Modulators:
The effect of NO may be beneficial or deleterious and both NO synthase (NOS) inhibitors and substrates of NOS could have great therapeutic potential in such steroid-resistant pathologic conditions as severe asthma and COPD.16 There are several reasons behind a considerable interest in the development of new compounds to act as NO donors for patients with lung diseases. NO plays an important role in bactericidal activity in the lungs, ciliary beating, and mucociliary dysfunction. Suppression of endogenous NO production by smoking in COPD might contribute to the recurrent chest infections in these patients. Therefore, an antiinflammatory treatment (for example, a combination of corticosteroids and NO donors) that preserves NO production may be an optimal in asthma and COPD.
NOS Substrates:
L-arginine supplementation has been studied in a variety of clinical situations in which the increase of NO production is desired. For example, orally administered and inhaled L-arginine has been used in normal subjects and patients with primary ciliary dyskinesia to improve the bactericidal activity of the lungs, ciliary beating, and mucociliary dysfunction in COPD.
Effect of ICS:
Lack of effect of conventional ICS on CALV14 brings an important advantage of MEFT FENO measurements in COPD for monitoring the inflammatory process that is clearly different from asthma. It can be speculated, however, that antiinflammatory effect of some novel formulation, for example, combination of beclomethasone dipropionate with formoterol delivered by small-particle-size aerosols, may be assessed by the MEFT in COPD.
Effect of Smoking:
Smoking may trigger this inflammatory cascade in COPD but does not have a direct effect on the source of CALV, which therefore may provide valuable additional information for assessing the inflammatory process. This may make this technique particularly valuable for assessing the antiinflammatory effects of new therapies in COPD in the future.
Exhaled Breath Condensate
Exhaled breath condensate (EBC) is collected by cooling or freezing exhaled air, a totally noninvasive technique. The collection procedure has been standardized,4 and there is strong evidence that abnormalities in EBC composition may reflect biochemical changes of airway lining fluid.18 Potentially, EBC can be used to measure the targets of modern therapy in clinical trials and to monitor asthma and COPD in the clinic.
Exhaled Breath Biomarkers in Clinical Research
Studying Mechanisms of Asthma and COPD:
Exhaled prostaglandin E2 and prostaglandin F2
in EBC are markedly increased in COPD but not in asthma.1920 In contrast, leukotriene E4 is increased in asthma but is not detectable in normal subjects or in patients with COPD.21 Therefore, exhaled breath profiles of various exhaled biomarkers may be used to differentiate their different pathophysiology.
Nonselective cyclooxygenase (COX) inhibition decreases PGE2 and increases leukotriene B4 (LTB4) in EBC in COPD, whereas selective COX-2 inhibition has no effect on these eicosanoids.22 This suggests that there is a specific mechanism behind the COX inhibition and redirection of arachidonic acid metabolism toward the 5-lipoxygenase pathway, which can be studied noninvasively in patients with COPD.21
EBC Use in General Practice:
Concentrations of LTB4 are increased in EBC of patients with stable COPD and COPD exacerbations, and returns to normal during the recovery period.23 Interestingly, LTB4 levels fell after antibiotic treatment and became similar to the levels in normal nonsmoking subjects, reflecting a fall in neutrophil markers in the airways during the recovery period. Furthermore, LTB4 levels fell further after 2 months in patients who had no further exacerbations, which suggests that exhaled LTB4 may be useful in the noninvasive assessment and monitoring of inflammation in patients with COPD.
Potentially, hydrogen ions (pH) can be measured in EBC as a simple acidification marker that is highly reduced in acute asthma24 and is low in COPD. There is increasing evidence that dilution of respiratory droplets in water and potential contamination with ammonia generated in the mouth25 may be largely ignored.
Exhaled Breath Temperature and Bronchial Blood Flow
Exhaled breath temperature and bronchial blood flow may reflect rubor and calor in the airways, and therefore may be markers of tissue inflammation and remodeling in asthma and COPD. The fact that lower breath temperature, after the inhalation of corticosteroids, is correlated with reduced levels of bronchial blood flow26 may suggest that these noninvasive measurements may be useful to evaluate airway inflammation and may provide a tool to assess steroid sensitivity.
Other Novel Technologies for Exhaled Biomarkers Assessment
Proteomics and Metabonomics
These noninvasive technologies offer rapid, mechanistic information of response of living systems to any exposure (smoke, bacterial/viral, treatment) regarding protein expression or metabolic regulation. They may facilitate incorporation of clinical data at earlier stages of drug development and particularly aid biomarker discovery and characterization.
Combination Biomarkers
Recently, it has been shown that young asthmatics with normal lung function but significant airway inflammation (FENO, 87.3 parts per billion)27 had different degree of abnormality of chemokines and LTB4 levels measured both in blood and in EBC. This may suggest that exhaled "combined biomarkers" will be able differentiate the degree of local vs systemic inflammation. Combination biomarkers (combination of the strength of the EBC approach and exhaled NO, for example) may be necessary to make some prevalently research-orientated biomarkers more practical.
Small Molecules Detection ("Electronic Nose")
Smell or odor has been used as a symptom of disease for centuries. Recently, patterns of biochemical markers have been found in the exhaled breath of patients with lung and breast cancers that are distinguishable from those of control subjects. However, trained household dogs were able to detect biopsy-confirmed lung and breast cancer with 0.99 and 0.88 specificity, respectively.28 We have recently started our own program based on atmospheric pressure ionization spectrometry to examine the chemistry of exhaled breath to identify which chemical compounds can most accurately identify asthma and COPD, including patients with and without bacterial exacerbations.
Future Directions
At this time, single exhaled markers are usually evaluated in isolation; but as indicated above, markers are affected differently in different diseases, and different markers vary in their sensitivity to certain maneuvers, such as the effect of therapy. These differences may be exploited in the future as more markers are characterized, so that each disease may have a characteristic profile or fingerprint of different markers that may be diagnostic in asthma and COPD. Treatments too may impose a characteristic effect on these markers, and this may improve the specificity of treatment in the future, particularly as more potent and specific treatments become available.
Footnotes
Abbreviations: CALV = peripheral nitric oxide; COX = cyclooxygenase; EBC = exhaled breath concentrate; FENO = fractional exhaled nitric oxide; ICS = inhaled corticosteroids; iNOS = inducible NO synthase; LTB4 = leukotriene B4; MEFT = multiple exhalation flow technique; NO = nitric oxide; NOS = NO synthase
Dr. Kharitonov is a member of scientific advisory boards for Aerocrine, and has received lecture fees from Aerocrine, AstraZeneca, MSD, and research grants from GlaxoSmithKline, AstraZeneca, Duska, MSD, and Aerocrine.
Dr. Barnes has reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Received for publication April 11, 2006. Accepted for publication August 7, 2006.
References
This article has been cited by other articles:
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  K. G. Lim and C. Mottram The Use of Fraction of Exhaled Nitric Oxide in Pulmonary Practice Chest, May 1, 2008; 133(5): 1232 - 1242. [Abstract] [Full Text] [PDF]
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W. J. Piotrowski, A. Antczak, J. Marczak, A. Nawrocka, Z. Kurmanowska, and P. Gorski Eicosanoids in Exhaled Breath Condensate and BAL Fluid of Patients With Sarcoidosis Chest, August 1, 2007; 132(2): 589 - 596. [Abstract] [Full Text] [PDF]
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