© 2006 American Thoracic Society doi: 10.1164/rccm.2512001
Exhaled Breath Condensate pHReflecting Acidification of the Airway at All LevelsUniversity of Virginia, Charlottesville, Virginia Airway lining fluid acidification can and does affect airway function by numerous pathways, including damaging epithelial cells, enhancing oxidative injury, decreasing ciliary motility, altering inflammatory cell recruitment and function, and triggering cough and bronchospasm (1). Airway acidification occurs when gastric acid is aspirated (2), and is a likely mechanism of lung injury associated with chlorine gas inhalation (3), which symptomatically behaves much like acute asthma. Acidification is a common finding in inflamed fluids throughout the body, and it is reasonable to expect the same in the lung in asthma and other inflammatory airway diseases. Obtaining direct data regarding airway lining fluid pH in health and, more particularly, in acute disease is fraught with difficulties arising from the poorly accessible and large surface area of the lungs, and the invasiveness of passing pH probes. Assays of the pH of exhaled breath condensate (EBC) therefore have been used in an attempt to overcome the nearly complete lack of understanding we have regarding this central, and therapeutically addressable, chemical characteristic of the airways and lungs. EBC can be collected safely even from critically ill patients, and EBC pH has been found to be low in multiple lung diseases. As with any assay or procedure, caution is warranted regarding the interpretation of EBC pH, and there needs to be awareness of factors that can influence this measurement. That EBC acidification reflects lower respiratory tract disease is supported by several arguments: (1) low EBC pH is found in diseases of the lower airway and lung, such as asthma (4) and COPD (5), in which salivary acidification is not a known component; (2) low EBC pH is identified in samples collected from the isolated lower airway (6, 7) in endotracheally intubated, ill patients; and (3) EBC pH correlates with lower airway acidification measured directly by pH probe placed against the epithelium, at least in the cow (8). It is clear that acidification of the airway at any level, including the hypopharynx, oropharynx, or tracheobronchial tree, could cause volatilization of acids that are then exhaled. In consideration of this potential for upper airway contamination, it is common practice to avoid collecting EBC samples within an hour of eating or drinking so as to prevent effects of acidic food or drink. In this issue of the AJRCCM (pp. 386–392), Effros and coworkers provide some data in an effort to directly support what was previously assumed: that salivary acids, in addition to lower airway acids, also could contribute to EBC acidification (9). Exhaled breath passes through the hypopharynx and oropharynx unless there is an artificial airway. How can these portions of human anatomy then not have potential to contribute to exhaled breath assays? Certainly, if breath sampling were ever to be used as a method of assessing salivary pH, one would expect substantial and perhaps overwhelming contamination from the much greater surface area of the lungs, so it is fair to consider the obverse. Despite the title of the Effros study, their data, like those of previous studies using oral EBC collections, do not allow for completely confident discrimination among salivary, hypopharyngeal, or lung sourcing of the acids. No effort was made to bypass the oropharynx and hypopharynx in this study, and the acids could be derived from any location in the airway and lungs. Of note, when the oral airway has been bypassed with endotracheal intubation in other studies, EBC pH has found to be the same as in oral collections (10), suggesting that the saliva was not an important determinant of the breath assay results in these patients. Some additional limitations of this study should be noted. There were only 10 patients with chronic obstructive pulmonary disease (COPD) enrolled in this study, and the EBC sampling and non–gas-standardized pH assay methodology these investigators used have been replaced by other investigators because of problems with both salivary and CO2 contamination. These issues are not sufficiently addressed in the current study. No effort was made to control for CO2, and there is reliance on an amylase activity assay not validated in EBC. The conclusions about EBC pH that are made in this article therefore should not improperly be extended to studies using other collection equipment and more validated gas-standardized EBC pH assays. These concerns do not diminish the important point that orally collected EBC effectively samples more than just the lower airway. That EBC pH can be reduced by acidification of the upper airway structures may be a very useful asset. It is a bit difficult to conceive of COPD as a disease of salivary acidification. It is more conceivable that during the prolonged (1 h) breath sampling in this particular study, these patients with COPD had episodic acidic reflux into their laryngopharyngeal airway, and that this is what Effros and colleagues identified with their EBC collection methodology. Some mild correlation with salivary pH (which has not been seen in previous studies using shorter collection times [10]) would more likely then be found. Given the insufficiency of current reflux diagnostics in the setting of respiratory symptoms, the value of EBC pH in identifying acid reflux as relevant to cough should be welcomed. Indeed, its research and clinically utility is already being demonstrated (11). However, the fact that the lower airway is clearly capable of acidifying without reflux is not to be minimized. Airway epithelial cells can actively acidify their extracellular fluid, and they have been shown to be capable of doing just that (12). It seems likely that in COPD (and asthma) the lower airway does acidify, acid reflux to the hypopharynx does occur, and the saliva can acidify. These causes of EBC acidification can be identified and may be differentiated by examining symptoms in association with EBC pH profiles derived from sequential breath sampling, while using a well-validated gas-standardized pH assay. Acid reflux as a proximate cause of respiratory symptoms may be distinguished from persistent inflammation by the transience (minutes) of airway acidification after a reflux event compared with a more persistently low pH value in the setting of inflammation, and this may be a particularly useful investigation in the setting of chronic cough. FOOTNOTES Conflict of Interest Statement: J.H. is a cofounder of Respiratory Research, Inc., and has intellectual property interest in exhaled breath condensate pH measurement. The University of Virginia (UVA) Patent Foundation owns intellectual property relating to exhaled breath condensate pH assays, and has licensed that technology to Respiratory Research, Inc., which is a UVA faculty start-up company founded in part by J.H. Respiratory Research has subcontracted UVA to perform a clinical study involving exhaled breath pH assays. REFERENCES
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