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Original Research: Miscellaneous |

Normative Data for pH of Exhaled Breath Condensate* FREE TO VIEW

Alix O. Paget-Brown, MD; Lina Ngamtrakulpanit, MD; Alison Smith, BA; Dorothy Bunyan; Stephanie Hom, BS; Ashley Nguyen, BA; John F. Hunt, MD
Author and Funding Information

*From the Divisions of Neonatology (Dr. Paget-Brown) and Respiratory Medicine (Ms. Smith, Ms. Bunyon, Ms. Hom, Ms. Nguyen, and Dr. Hunt), Department of Pediatrics, University of Virginia, Charlottesville, VA.

Correspondence to: John Hunt, MD, Assistant Professor of Pediatrics, Box 800386, University of Virginia, Charlottesville, VA 22908; e-mail: Jfh2m@virginia.edu



Chest. 2006;129(2):426-430. doi:10.1378/chest.129.2.426
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Published online

Introduction: Measurement of pH is one of the simplest and most technically validated biomarkers studied in exhaled breath condensate (EBC). The pH of EBC has been found to be lower than controls in many respiratory disorders. Published data from normal control subjects have been reasonably consistent, but the data sets are not large. This study was undertaken to establish normative EBC pH reference values.

Participants: Four hundred four healthy subjects of all ages were enrolled.

Interventions: Each participant provided a single EBC sample using a disposable collector at modest temperature so that EBC was collected as a liquid.

Measurements and results: Samples of EBC were bubbled with argon gas to standardize for carbon dioxide, and pH was recorded with a calibrated and validated glass microelectrode on stabilization. The median EBC pH was 8.0 with interquartile (25 to 75%) range of 7.8 to 8.1. There were no differences based on age, sex, or race. The distribution is skewed, with 6.4% of EBC samples having a pH range < 7.4.

Conclusions: An extensive normal data set now exists that reveals EBC pH is maintained in a modestly alkaline and tight range in subjects who consider themselves healthy.

Figures in this Article

Measurement of the pH of body fluids has a long and successful history in clinical diagnosis. Exhaled breath condensate (EBC) pH has recently been added to the list as a useful assessment relevant to lung disease diagnosis and management. EBC pH was initially noted to be abnormally low during acute asthma exacerbations.1It was subsequently recognized that EBC pH is low in diverse respiratory disease states, including asthma, COPD, chronic cough, bronchiectasis, ARDS, and others.28 EBC pH correlates with other indexes of airway inflammation.2 Beyond being simply a biomarker of disease status, low EBC pH has provided data supporting the important role of airway acid stress in respiratory diseases.9

Two methods of reporting EBC pH have been included in the literature: (1) measurement of pH after gas standardization (sometimes called “deaeration”) to equilibrate EBC with a CO2-free gas; and (2) measurement of pH without this gas standardization step. Although the data from these two different systems may correlate, the resulting pH values are different, and they need to be understood as having different meanings. EBC pH measurement is perhaps the most technically validated of all measurements performed to date on EBC, with diverse subject, collection, storage, and assay system variations having been evaluated.1012 There are multiple published articles presenting normal control data in small numbers of subjects (Table 1 ). In this article, we present data from 404 self-reported healthy volunteers as a normal reference range for gas standardized EBC pH. Because the EBC pH measurement reproducibly can be performed in laboratories throughout the world, we believe this reference database will serve to enhance interlaboratory communication.

Subjects

Self-described healthy volunteers were recruited from the area surrounding the University of Virginia in the United States. This is a mixed community of urban, suburban, and rural families. To ensure that the population would serve as the most useful control group, subjects were excluded from the study if they affirmed on screening that they smoked tobacco or had any of the following symptoms or diseases: chronic cough, recurrent or chronic wheeze, COPD, emphysema, chronic bronchitis, cystic fibrosis, asthma, recurrent bronchitis, chronic nasal or sinus conditions, or any other respiratory symptom or condition. Subjects were excluded if they were experiencing viral respiratory tract (common cold) symptoms. Additional exclusion criteria included physician-diagnosed gastroesophageal reflux disease, use of antacids, histamine type 2 antagonists, or proton pump inhibitors in the past week, or if the subject admitted to any acute or chronic systemic illness. All subjects signed informed consent documents, and the study was approved by the University of Virginia Human Investigation Committee.

Sample Collection

Samples of EBC were collected during oral tidal breathing for 7 min using a disposable portable collector (Rtube; Respiratory Research Inc; Charlottesville, VA). Subjects did not wear nose clips and reported that they had ingested no liquids or solids in the previous 1 h. The metal sleeves used to chill the breath condenser surface were stored at approximately − 10°C prior to use, a temperature shown to lead to EBC collection as a liquid, not as a solid, on the condenser surface. The majority of samples were collected under supervised conditions, although samples were also collected unsupervised at home.

Sample Handling and Assay

EBC samples were frozen as soon as possible after collection at – 20°C until assay, which was usually performed within 1 week. Each sample was thawed, removed from the portable collector by plunging, and then aliquoted into several microcentrifuge tubes. Argon gas (350 mL/min) was bubbled for 8 min through a 200-μL aliquot of EBC by means of a glass Pasteur pipette inserted into the sample. EBC was kept in constant motion by this process, maximizing exposure of the fluid to the CO2-free gas. This amount of time was previously shown to be sufficient for complete stabilization of sample pH in previous experiments.1,11 pH was measured using an Orion glass combination micro pH electrode attached to a Orion 525-A pH meter (Thermo Electron Corporation; Waltham, MA). This pH measurement system was calibrated at pH 4, pH 7, and pH 10 against standard as well as low-ionic-strength calibration buffers prior to each series of assays.

Statistical Analysis

Data are reported as median and interquartile range (25 to 75%), as well as 5 to 95% ranges and full ranges. For comparisons between sexes and among age ranges and races, analysis was performed by rank-sum testing or analysis of variance on ranks with appropriate pair-wise comparisons using software (Sigmastat 3.0; Systat Software; Point Richmond, CA).

Four hundred twelve subjects were enrolled and provided a single EBC sample for this study. The subject population is described in Table 2 . Of the 412 subjects enrolled, 404 provided sample volumes sufficient for EBC pH assay, a success rate > 98%.

The median EBC pH of this healthy population was 8.0 with interquartile (25 to 75%) range of 7.8 to 8.1 (Fig 1 ). The maximum EBC pH was 8.4, and the minimum pH was 4.5. The values were the same for female patients (median, 8.0; interquartile range, 7.8 to 8.1; n = 248) and male patients (median, 8.0; interquartile range, 7.9 to 8.1; n = 154; p = 0.31) [Fig 2 ]. EBC pH values for 10-year age brackets were determined (Table 2; Fig 3 ), and again these medians were 8.0 to 8.1 with no differences identified by analysis of variance on ranks (p = 0.27). EBC pH ≤ 7.3 accounted for 6.4% of the samples.

In this study, we have demonstrated that in healthy subjects, the median, gas-standardized EBC pH is 8.0 with an interquartile range of 7.8 to 8.1. The data are tightly clustered in a mildly nonparametric bell curve. This normal range provides additional context to the published data revealing prominently lower values in patients with multiple respiratory disease states (with EBC pH often in the pH 4 to 6 range).13,5,78,1214 Our data present a range that is slightly higher than that from previously published control subjects, which in part reflects that means ± SD are more commonly reported and the mean is brought down by control outliers. The mean pH of this current data set is 7.85, consistent with previous data (although this data set is not parametric). Some prior studies may have performed the gas standardization less completely than is currently done.

Several lines of thought help to convince us that a low EBC pH reflects low pH of the fluid lining the airways. It is expected that acidification of the airway at any level will allow protonation, volatilization, and exhalation of acids that would otherwise be trapped in the airway as conjugate anionic bases. Exhaled water-soluble acids are then trapped in EBC and lower its pH. In separate studies, EBC pH from healthy subjects has been found to be very similar to tracheobronchial secretion pH15and the airway lining fluid pH when measured by pH probe invasively.1618 The airway has been directly measured to have a profoundly low pH in the presence of laryngopharyngeal acid reflux, revealing a ready ability to aspirate acid into the lungs and drop pH of the tracheal lining fluid to as low as 2.19 Our study population ages are skewed toward the younger decades, which is similar to the skewing of the healthy population near our medical center, which is overwhelmingly dominated by the students of the University of Virginia.

The ability to collect data from this large study population was enhanced by the brevity of the subject time commitment; for this purpose, the only enrollment exclusion criteria were based on a brief health questionnaire. Our study was limited because we were not able to obtain data regarding spirometry, bronchial hyperreactivity, allergy skin tests, chest radiographs, exercise tolerance, or esophageal pH probes/manometry to help ensure lack of disease in those who were not excluded by the questionnaire. The wider interquartile range and lower 5% cutoff in the young age study groups may reflect a true difference in their normal range, or speculatively may result from artifacts from oral ingestion or acid reflux not as well reported by these subjects.

Gas standardization by bringing EBC into equilibrium with a CO2-free gas has been employed in many of the studies of EBC pH, but not all. Technical validation has been primarily performed using gas standardization, however. The gas-standardized pH of EBC is a very simple assay of an easy-to-collect fluid. It is immune to storage, transport, timing of assay, and other characteristics that could otherwise make data collection difficult. EBC pH is not affected by the age of the subject.

Some investigators are concerned that CO2 should not be removed from EBC because CO2 (and resulting carbonic acid) is a relevant acid in the airway and should not be ignored. However, when collecting EBC for pH assay, we are primarily interested in identifying the presence of acids that are volatile specifically from an acidic source fluid. The volatility of CO2 is not appreciably dependent on the pH of the source fluid within the range relevant to the airway, and therefore the levels of CO2 in EBC tell us little about the pH of the source fluid. In regards to EBC pH, CO2 represents an unwelcome noise that gas standardization well addresses. Gas standardization is a key component that allows EBC collection for pH assay to be particularly useful and easy for clinical studies.

Data have been published specifically testing and refuting speculations that EBC pH may be an artifact of hyperventilation or oral ammonia.11,20Data supporting that EBC pH well represents airway lining fluid pH are forthcoming. The airway must be considered to include the laryngopharynx as a potential source of acids in EBC. Indeed, any cause of airway acidification at any level can affect EBC pH values. Thus laryngopharyngeal acid reflux—with or without acid aspiration into the lower airway—may contribute to EBC acidification in samples collected with oral exhalation. Given that patients with obstructive lung disease have a high incidence of acid reflux,21 this pathway for EBC acidification needs to be kept in mind. It is important to note, however, that measurement of EBC pH from isolated lower airway samples have revealed specific lower airway acidification, supporting the ability of the airway to acidify in the absence of laryngopharyngeal acid reflux.6,8

It is likely that there was some inclusion of subjects with unidentified respiratory disease or laryngopharyngeal acid reflux, and these factors may provide an explanation for why EBC pH is occasionally low in seemingly healthy subjects. If the saliva or hypopharynx is sufficiently acidified by drinking an acidic beverage, then EBC pH will be low until this acidic challenge is neutralized. In this, and all of our studies, we collect EBC sample only if the subjects state they have not consumed anything in the previous 60 min; however, subjects may not always accurately reveal recent ingestion, and thus acidic ingestion artifact may account for some low EBC pH values.

As a noninvasive biomarker relevant to respiratory disease, EBC pH has many positive attributes. Intrasample reproducibility is excellent.12 As we have reported previously, reproducibility of the measurement within day and between days in healthy subjects is high and is not affected by hyperventilation, sample storage duration, or collection orally or by endotracheal tube.11 The high level of accuracy of EBC pH measurement is in part the result of decades of advances in measurement of this standard chemical property. There are readily available technological capabilities to assess concentrations of hydrogen ions as low as 10 fmol/L (which is equivalent to a very alkaline pH of 14) and as high as 1 mol/L (a very acid pH of 0). Measurement of pH is routinely performed in dilute aqueous fluids such as EBC and even in highly purified water such as used in steam turbines. In EBC, concentrations of hydrogen ions unequivocally are in the useful range of available assays, and the level of assay detection is therefore not a limiting factor. Due to the nature of EBC, the effective pH probe either will be designed specifically for low-ionic-strength fluids, or be proven to work in them by calibrating in low-ionic-strength buffer identically to normal pH buffers, and by stabilizing rapidly in EBC.

It is important to note that these reference data are applicable for the methodology we employed but should be extended to other methodology with some caution. For example, we collected EBC as a liquid, not as an ice. It is possible that collection as an ice may decrease trapping of relevant volatile acids and make the assay less sensitive to airway acidification. We employed a single-use disposable collection system that was never exposed to detergents or other agents that might not be fully removed by rinsing. We make efforts to collect sample only when subjects consumed no food or drink for 1 h prior to collection. These issues should be considered as investigators design studies involving EBC pH.

Importantly, consideration should be given to the possibility that a low EBC pH value in a given subject might reflect either laryngopharyngeal acidification or lower airway acidification or both. Longitudinal assessment (multiple samples during a day) will help to distinguish these possibilities.

This work along with previous published data11 reveal that gas standardized EBC pH is a particularly robust assay that is not systematically affected by patient age or sex, nor by duration or volume of sample collection, nor by presence of methacholine-induced airflow obstruction, nor by extended sample storage. Only alterations in airway pH, at some level, appear to affect the EBC measurement when performed using our methodology.

Given that invasive measures of airway pH are rarely performed and provide only very focal data, EBC pH remains the most readily available method to study the contribution of airway acid stress to respiratory disease. The healthy subject reference data reported in this study should serve as normative data for comparison purposes as others investigate EBC pH, airway acid stress, and laryngopharyngeal acid reflux in patients with diverse respiratory diseases.

Abbreviation: EBC = exhaled breath condensate

Dr. Hunt is a co-founder of Respiratory Research, Inc, the company that manufactures the EBC collectors used in this study. This company and the University of Virginia own patents relating to collection of and pH measurement in EBC.

Table Graphic Jump Location
Table 1. Articles Presenting Normal Control Data*
* 

Data are presented as

 

mean ± SD,

 

mean±SEM median (interquartile range), or absolute No.

Table Graphic Jump Location
Table 2. EBC pH by Decade of Life
Figure Jump LinkFigure 1. Distribution of EBC pH values in 404 healthy subjects. Median EBC pH is 8.0 (interquartile range, 7.8 to 8.1). Samples were collected for 7 min using a disposable commercially available polypropylene collector at temperatures that ensured condensation in liquid phase as opposed to as ice crystals.Grahic Jump Location
Figure Jump LinkFigure 2. EBC pH values for healthy female and male subjects.Grahic Jump Location
Figure Jump LinkFigure 3. EBC pH values separated based on decade of life.Grahic Jump Location
Hunt, JF, Fang, K, Malik, R, et al (2000) Endogenous airway acidification: implications for asthma pathophysiology.Am J Respir Crit Care Med161,694-699. [PubMed]
 
Kostikas, K, Papatheodorou, G, Ganas, K, et al pH in expired breath condensate of patients with inflammatory airway diseases.Am J Respir Crit Care Med2002;165,1364-1370. [CrossRef] [PubMed]
 
Carraro, S, Folesani, G, Corradi, M, et al Acid-base equilibrium in exhaled breath condensate of allergic asthmatic children.Allergy2005;60,476-481. [CrossRef] [PubMed]
 
Ojoo, JC, Mulrennan, SA, Kastelik, JA, et al Exhaled breath condensate pH and exhaled nitric oxide in allergic asthma and in cystic fibrosis.Thorax2005;60,22-26. [CrossRef] [PubMed]
 
Niimi, A, Nguyen, LT, Usmani, O, et al Reduced pH and chloride levels in exhaled breath condensate of patients with chronic cough.Thorax2004;59,608-612. [CrossRef] [PubMed]
 
Moloney, ED, Mumby, SE, Gaidocsi, JH, et al Exhaled breath condensate detects markers of pulmonary inflammation after cardiothoracic surgery.Am J Respir Crit Care Med2004;169,64-69. [PubMed]
 
Carpagnano, GE, Barnes, PJ, Francis, J, et al Breath condensate in children with cystic fibrosis and asthma: a new noninvasive marker of airway inflammation?Chest2004;125,2005-2010. [CrossRef] [PubMed]
 
Gessner, C, Hammerschmidt, S, Kuhn, H, et al Exhaled breath condensate acidification in acute lung injury.Respir Med2003;97,1188-1194. [CrossRef] [PubMed]
 
Ricciardolo, FL, Gaston, B, Hunt, J Acid stress in the pathology of asthma.J Allergy Clin Immunol2004;113,610-619. [CrossRef] [PubMed]
 
McCafferty, JB, Bradshaw, TA, Tate, S, et al Effects of breathing pattern and inspired air conditions on breath condensate volume, pH, nitrite, and protein concentrations.Thorax2004;59,694-698. [CrossRef] [PubMed]
 
Vaughan, J, Ngamtrakulpanit, L, Pajewski, TN, et al Exhaled breath condensate pH is a robust and reproducible assay of airway acidity.Eur Respir J2003;22,889-894. [CrossRef] [PubMed]
 
Borrill, Z, Starkey, C, Vestbo, J, et al Reproducibility of exhaled breath condensate pH in chronic obstructive pulmonary disease.Eur Respir J2005;25,269-274. [CrossRef] [PubMed]
 
Tesse, R, Miniello, VL, Fiermonte, P, et al Exhaled breath condensate (EBC) pH measurement in children with atopic dermatitis (AD): a new diagnostic tool to monitor the allergy march. Melloni Paediatria. 2004;; Abstract6.
 
Rosias, PP, Dompeling, E, Dentener, MA, et al Childhood asthma: exhaled markers of airway inflammation, asthma control score, and lung function tests.Pediatr Pulmonol2004;38,107-114. [CrossRef] [PubMed]
 
Metheny, NA, Stewart, BJ, Smith, L, et al pH and concentration of bilirubin in feeding tube aspirates as predictors of tube placement.Nurs Res1999;48,189-197. [CrossRef] [PubMed]
 
Patel, PH, Thomas, E, Willis, M, et al Inadvertent bronchial pH monitoring [letter]. Gastrointest Endosc. 1987;;33 ,.:465
 
Donnelly, RJ, Berrisford, RG, Jack, CI, et al Simultaneous tracheal and esophageal pH monitoring: investigating reflux-associated asthma.Ann Thorac Surg1993;56,1029-1033;discussion 1034. [CrossRef] [PubMed]
 
Jack, CI, Walshaw, MJ, Tran, J, et al Twenty-four-hour tracheal pH monitoring: a simple and non-hazardous investigation.Respir Med1994;88,441-444. [CrossRef] [PubMed]
 
Jack, CI, Calverley, PM, Donnelly, RJ, et al Simultaneous tracheal and oesophageal pH measurements in asthmatic patients with gastro-oesophageal reflux.Thorax1995;50,201-204. [CrossRef] [PubMed]
 
Wells, K, Vaughan, J, Pajewski, TN, et al Exhaled breath condensate pH assays are not influenced by oral ammonia.Thorax2005;60,27-31. [CrossRef] [PubMed]
 
Harding, SM Gastroesophageal reflux as an asthma trigger: acid stress.Chest2004;126,1398-1399. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Distribution of EBC pH values in 404 healthy subjects. Median EBC pH is 8.0 (interquartile range, 7.8 to 8.1). Samples were collected for 7 min using a disposable commercially available polypropylene collector at temperatures that ensured condensation in liquid phase as opposed to as ice crystals.Grahic Jump Location
Figure Jump LinkFigure 2. EBC pH values for healthy female and male subjects.Grahic Jump Location
Figure Jump LinkFigure 3. EBC pH values separated based on decade of life.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Articles Presenting Normal Control Data*
* 

Data are presented as

 

mean ± SD,

 

mean±SEM median (interquartile range), or absolute No.

Table Graphic Jump Location
Table 2. EBC pH by Decade of Life

References

Hunt, JF, Fang, K, Malik, R, et al (2000) Endogenous airway acidification: implications for asthma pathophysiology.Am J Respir Crit Care Med161,694-699. [PubMed]
 
Kostikas, K, Papatheodorou, G, Ganas, K, et al pH in expired breath condensate of patients with inflammatory airway diseases.Am J Respir Crit Care Med2002;165,1364-1370. [CrossRef] [PubMed]
 
Carraro, S, Folesani, G, Corradi, M, et al Acid-base equilibrium in exhaled breath condensate of allergic asthmatic children.Allergy2005;60,476-481. [CrossRef] [PubMed]
 
Ojoo, JC, Mulrennan, SA, Kastelik, JA, et al Exhaled breath condensate pH and exhaled nitric oxide in allergic asthma and in cystic fibrosis.Thorax2005;60,22-26. [CrossRef] [PubMed]
 
Niimi, A, Nguyen, LT, Usmani, O, et al Reduced pH and chloride levels in exhaled breath condensate of patients with chronic cough.Thorax2004;59,608-612. [CrossRef] [PubMed]
 
Moloney, ED, Mumby, SE, Gaidocsi, JH, et al Exhaled breath condensate detects markers of pulmonary inflammation after cardiothoracic surgery.Am J Respir Crit Care Med2004;169,64-69. [PubMed]
 
Carpagnano, GE, Barnes, PJ, Francis, J, et al Breath condensate in children with cystic fibrosis and asthma: a new noninvasive marker of airway inflammation?Chest2004;125,2005-2010. [CrossRef] [PubMed]
 
Gessner, C, Hammerschmidt, S, Kuhn, H, et al Exhaled breath condensate acidification in acute lung injury.Respir Med2003;97,1188-1194. [CrossRef] [PubMed]
 
Ricciardolo, FL, Gaston, B, Hunt, J Acid stress in the pathology of asthma.J Allergy Clin Immunol2004;113,610-619. [CrossRef] [PubMed]
 
McCafferty, JB, Bradshaw, TA, Tate, S, et al Effects of breathing pattern and inspired air conditions on breath condensate volume, pH, nitrite, and protein concentrations.Thorax2004;59,694-698. [CrossRef] [PubMed]
 
Vaughan, J, Ngamtrakulpanit, L, Pajewski, TN, et al Exhaled breath condensate pH is a robust and reproducible assay of airway acidity.Eur Respir J2003;22,889-894. [CrossRef] [PubMed]
 
Borrill, Z, Starkey, C, Vestbo, J, et al Reproducibility of exhaled breath condensate pH in chronic obstructive pulmonary disease.Eur Respir J2005;25,269-274. [CrossRef] [PubMed]
 
Tesse, R, Miniello, VL, Fiermonte, P, et al Exhaled breath condensate (EBC) pH measurement in children with atopic dermatitis (AD): a new diagnostic tool to monitor the allergy march. Melloni Paediatria. 2004;; Abstract6.
 
Rosias, PP, Dompeling, E, Dentener, MA, et al Childhood asthma: exhaled markers of airway inflammation, asthma control score, and lung function tests.Pediatr Pulmonol2004;38,107-114. [CrossRef] [PubMed]
 
Metheny, NA, Stewart, BJ, Smith, L, et al pH and concentration of bilirubin in feeding tube aspirates as predictors of tube placement.Nurs Res1999;48,189-197. [CrossRef] [PubMed]
 
Patel, PH, Thomas, E, Willis, M, et al Inadvertent bronchial pH monitoring [letter]. Gastrointest Endosc. 1987;;33 ,.:465
 
Donnelly, RJ, Berrisford, RG, Jack, CI, et al Simultaneous tracheal and esophageal pH monitoring: investigating reflux-associated asthma.Ann Thorac Surg1993;56,1029-1033;discussion 1034. [CrossRef] [PubMed]
 
Jack, CI, Walshaw, MJ, Tran, J, et al Twenty-four-hour tracheal pH monitoring: a simple and non-hazardous investigation.Respir Med1994;88,441-444. [CrossRef] [PubMed]
 
Jack, CI, Calverley, PM, Donnelly, RJ, et al Simultaneous tracheal and oesophageal pH measurements in asthmatic patients with gastro-oesophageal reflux.Thorax1995;50,201-204. [CrossRef] [PubMed]
 
Wells, K, Vaughan, J, Pajewski, TN, et al Exhaled breath condensate pH assays are not influenced by oral ammonia.Thorax2005;60,27-31. [CrossRef] [PubMed]
 
Harding, SM Gastroesophageal reflux as an asthma trigger: acid stress.Chest2004;126,1398-1399. [CrossRef] [PubMed]
 
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