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ORIGINAL ARTICLE

Exhaled breath condensate pH decreases during exercise-induced bronchoconstriction ANDRAS BIKOV,1 GABRIELLA GALFFY,1 LILLA TAMASI,1 DORA BARTUSEK,1 BALAZS ANTUS,2 GYORGY LOSONCZY1 AND ILDIKO HORVATH1 1

Department of Pulmonology, Semmelweis University, and 2National Koranyi Institute of TB and Pulmonology, Budapest, Hungary

ABSTRACT Background and objective: Exercise-induced bronchoconstriction (EIB) is the temporary narrowing of the airways caused by physical exercise. Its exact pathophysiology is unclear; however, acute changes in airways pH may play a role. Exhaled breath condensate (EBC) pH was suggested as a surrogate indicator for airway acid–base status, but its value is also affected by volatile molecules and respiratory droplet dilution. The aim of the study was to assess changes in EBC pH during EIB. Methods: Twenty-two asthmatics who reported breathlessness following exercise and 16 healthy individuals participated in the study. Lung function test was performed and exhaled breath samples were collected for pH, dilution factor and volatile compound pattern measurements (Cyranose 320) pre-exercise and at 0, 10, 20 and 30 min after physical exercise challenge. Fractional exhaled nitric oxide was measured before exercise. Results: EIB developed in 13 asthmatic subjects. In these participants, but not in the EIB-negative asthmatics (P = 0.51), EBC pH reduced significantly during exercise (P = 0.01). In addition, changes in EBC pH were related to the degree of bronchospasm in the EIBpositive group (P = 0.01, r = 0.68). Exhaled volatile pattern became altered (P < 0.05) during exercise in all subjects (asthmatics and controls). EBC pH changes were not related to EBC dilution or volatile compound pattern alterations (P > 0.05). Conclusions: The development of EIB was related to acute changes of EBC pH, which suggest the role of airway pH decrease in the pathophysiology of EIB. Exercise-induced changes in exhaled biomarkers suggest methodological precautions to avoid physical exercise before performing exhaled breath tests. Key words: asthma, breath test, electronic nose, exerciseinduced bronchospasm, exhaled breath condensate pH.

Correspondence: Andras Bikov, Department of Pulmonology, Semmelweis University, Dios arok 1/C, Budapest, H-1125, Hungary. Email: [email protected] Received 7 July 2013; invited to revise 17 September 2013; revised 16 October 2013; accepted 24 December 2013 (Associate Editor: Neil Eves). © 2014 The Authors Respirology © 2014 Asian Pacific Society of Respirology

SUMMARY AT A GLANCE Exhaled breath condensate (EBC) pH was measured in asthmatics with and without exerciseinduced bronchoconstriction (EIB) as well as healthy individuals before and after physical exercise. EBC pH decreased only in EIB-positive asthmatics and was related to the degree of bronchospasm suggesting a possible role of airway pH reduction in EIB.

INTRODUCTION Exercise-induced bronchoconstriction (EIB) is the temporary narrowing of the airways caused by physical exercise.1 During exercise, hyperventilation leads to water loss from the airway lining fluid that is not fully compensated in EIB.2 This results in high airway osmolarity, which induces mediator release from inflammatory cells causing bronchoconstriction. Hyperventilation-associated airway drying occurs even in healthy subjects;3 however, this is compensated rapidly in presence of an intact epithelium. Damaged epithelial layer has been shown in EIB compared with asthmatics without EIB,2,4 and it was associated with inflammatory mediator release.5 In epithelial injury, not only the control of airway osmolarity, but other epithelial functions, such as acid–base regulation, can be affected.6,7 In healthy subjects, alkalization of the airways is presumably the physiological response to exercise.8–10 However, the temporal course of airway pH during the development of EIB has not been investigated before. Assessment of short-term changes in the airway acidity is difficult, as the direct sampling techniques (bronchoscopy and bronchoalveolar lavage) are invasive and may per se generate low-grade airway inflammation. Exhaled breath condensate (EBC) has been chosen to investigate short-term changes in airway mediator content, as it is non-invasive, can be repeated in short time intervals and the sampling does not influence the mediator concentration in the airways. Various biomolecules have been analysed in Respirology (2014) 19, 563–569 doi: 10.1111/resp.12248

564 EBC during EIB, including endothelin-1,11 adenosine12 or cysteinyl leukotrienes.13 EBC pH might reflect airway acidity; however, its value is also affected by volatile airway acids and bases.8,14 In addition, dilution of respiratory droplets by water vapour may also influence EBC pH.15 Therefore, EBC pH analyses should be performed in parallel with measurements of airway volatile compounds and respiratory droplet dilution. Notably, EBC pH shows considerable inter-individual variability, and there is no difference in EBC pH between stable asthmatic and healthy subjects.15 The analysis of trends in EBC pH changes rather than actual values are more informative, as decrease in condensate pH was reported during asthma exacerbation;16,17 however, EBC pH has not yet been analyzed during EIB. The aim of this study was to investigate the effect of physical exercise on EBC pH during the development of EIB in asthma.

METHODS Subjects Twenty-two asthmatic (34 ± 8 years, five men) and 16 healthy subjects (26 ± 8 years, six men) participated in the study. Asthma was diagnosed according to Global Initiative for Asthma guidelines and was confirmed by 12% and 200 mL of increase in forced expiratory volume in 1 s (FEV1) following administration of 400 μg salbutamol. All asthmatics reported exerciseinduced breathlessness or had positive exercise challenge test previously; 15 asthmatic patients had positive skin prick test for common allergens. Asthma was diagnosed newly in seven patients; these patients did not use any anti-asthmatic drugs. Among the remaining 15 subjects, seven patients were using inhaled corticosteroids regularly with an average daily dose of 432 ± 200 μg budesonide equivalent. In these subjects, inhaled corticosteroids were withdrawn for at least 2 weeks prior to the study and patients used only short-acting β2-agonists in case of breathlessness except for the day of measurement, when no medication was taken. Another eight subjects had only mild intermittent asthma, and they were considered controlled for 4 weeks before enrolment even without using maintenance anti-asthma medications. Eleven asthmatic patients were well controlled, seven partially controlled and four uncontrolled. After inhaled corticosteroid withdrawal for 2 weeks, all the seven asthmatics maintained to be well or partially controlled. None of the subjects was a smoker or had respiratory tract infection within the 6 weeks before the study. Study design Before exercise, EBC was collected for pH and dilution factor measurements, exhaled breath volatile compound pattern analysis was performed using an electronic nose, and fractional exhaled nitric oxide (FENO) and lung function were measured. Subjects then performed an exercise challenge test on a treadmill at Respirology (2014) 19, 563–569

A Bikov et al.

room temperature by inhaling room air according to the latest guidelines1. EBC collection, electronic nose and lung function measurements were repeated at 0, 10, 20 and 30-min post-exercise. Subjects were divided into two groups according to their response to exercise challenge. Patients were considered EIBpositive if the drop in FEV1 was ≥10% at any postexercise time point compared with the pre-exercise value.1 The study was approved by the University Ethics Committee (Semmelweis University, TUKEB 110/ 2007), and all subjects signed informed consent form prior to the measurements.

Breath tests and lung function measurements EBC was collected for 10 min using the Rtube device (Respiratory Research, Charlottesville, VA, USA). The chilling tube was cooled at −80°C prior to the collection. Condensate samples were stored immediately at −80°C until analysis. Condensate pH was measured with a glass-electrode (SV 20 Seveneasy, Mettler Toledo, Schwerzenbach, Switzerland) after 10 min of argon-deaeration with a coefficient of variation of 3%.15 Respiratory droplet dilution was estimated by the measurement of conductivity in vacuum- treated EBC samples as described previously.18 The coefficient of variation was 12%.15 Exhaled breath volatile compounds were collected after deep inhalation to total lung capacity and expiration at controlled flow rate (50 mL/sec) against resistance (15–20 cm H2O). Anatomic dead space was discarded and alveolar air was collected in Teflon-coated Mylar bags. Samples were processed immediately with an electronic nose (Cyranose 320, Smiths Detection, Pasadena, CA, USA). The results obtained with this method were shown to be reproducible within a day19 and over 8 weeks.20 FENO was measured with an electrochemical device (NIOX MINO, Aerocrine, Solna, Sweden) at 50 mL/s.21 Lung function was measured by a spirometer (PDD301/s, Piston, Budapest, Hungary). Three measurements were performed, and the highest of them was used.22 Statistical analysis Graphpad Prism 5.0 (GraphPad Software Inc., San Diego, CA, USA) and SPSS 15.0 (SPSS Inc., Chicago, IL, USA) were used for statistical analyses. Asthma control between EIB-positive and EIB-negative groups was compared with chi-square test. Data normality was tested with the Kolmogorov–Smirnov test, which showed that the distributions of FENO, EBC pH and EBC dilution values were non-parametric. Unpaired t-test and Mann–Whitney U-test were used to compare pre-exercise values of asthmatic and healthy subjects as well as EIB-positive and EIBnegative groups. Temporal changes of FEV1, volume, pH and dilution of EBC and exhaled volatile compounds were assessed by repeated-measures anova and Friedman tests followed by Dunnett’s and Dunn’s post-hoc tests. Areas under the curves (AUC) were © 2014 The Authors Respirology © 2014 Asian Pacific Society of Respirology

565

EBC pH in exercise-induced bronchospasm Table 1 Subject characteristics before exercise

FEV1; % pred. FENO; ppb EBC pH EBC dilution

Asthma (n = 22)

Healthy (n = 16)

P-value†

EIB-positive asthmatics (n = 13)

EIB-negative asthmatics (n = 9)

P-value‡

92 ± 14 20.0 (15.50–42.00) 7.96 (7.80–8.40) 1849 (919–2094)

98 ± 11 14.5 (9.5–18.0) 7.88 (7.47–8.07) 1561 (819–1942)

0.22 0.03 0.23 0.49

91 ± 17 22.0 (9.50–44.00) 8.02 (7.91–8.49) 1359 (674–2007)

94 ± 9 18.0 (15.50–42.00) 7.87 (7.39–8.16) 2557 (1492–2204)

0.72 0.84 0.11 0.12



Asthmatic subjects versus healthy controls. EIB-positive versus EIB-negative asthmatic groups. Data are expressed as median (inter-quartiles range) except for FEV1 where as mean ± standard deviation. EBC, exhaled breath condensate; EIB, exercise-induced bronchoconstriction; FENO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 s; ppb, particles per billion. ‡

calculated for EBC pH and FEV1 and Pearson correlation was used to determine association between the two AUC.12 The responses of 28 electronic nose sensors underwent data reduction (principal component (PC) analysis) after the exclusion of the four watersensitive sensors (sensors 5, 6, 23 and 31). The PC were ordered by their initial eigenvalues, and the highest three were used (PC1, PC2, PC3). Mahalanobis distance, a stepwise classification technique was applied to classify cases into categorical divisions before exercise. The sample size was estimated to assess exerciseinduced EBC pH changes along five time points (1 pre-exercise and 4 post-exercise) in asthmatic subjects with an effect size of 0.25 and a power of 0.8.23 A P-value 0.05, Fig. 1). Exercise did not change EBC pH in healthy subjects significantly (P = 0.88). An exercise-induced EBC pH decrease was observed only in the EIB-positive subgroup (P = 0.01), with a significant difference at 10, 20 and 30-min post-exercise compared with preexercise. There was no change in EIB-negative patients (P = 0.51; Table 2, Fig. 2). There was a significant relationship between the changes in EBC pH and the degree of bronchospasm in the EIB-positive group (P = 0.01, r = 0.68, Fig. 3), but not in healthy (P = 0.42) or EIB-negative (P = 0.35) individuals. There was a significant change in exhaled volatile compound pattern following exercise in both asthmatic and healthy subjects (PC3, P < 0.05). The Respirology (2014) 19, 563–569

566 Table 2

A Bikov et al. Exercise-induced EBC pH changes

Healthy (n = 16) EIB-positive (n = 13) EIB-negative (n = 9)

Before exercise

0-min post-exercise

10-min post-exercise

20-min post-exercise

30-min post-exercise

P-value

7.88 (7.47–8.07) 8.02 (7.91–8.49) 7.87 (7.39–8.16)

7.79 (7.71–8.00) 8.06 (7.87–8.15) 7.84 (7.40–8.17)

7.85 (7.57–7.93) 7.92* (7.52–8.10) 8.06 (7.75–8.31)

7.82 (7.66–8.09) 7.85* (7.65–8.03) 7.87 (7.57–8.26)

7.86 (7.54–8.01) 7.69** (7.47–7.88) 8.04 (7.91–8.17)

0.88 0.01 0.51

* P < 0.05, ** P < 0.01 compared with the pre-exercise value assessed by Dunn’s post-hoc test. EBC pH values are expressed as median (inter-quartiles range). EBC, exhaled breath condensate; EIB, exercise-induced bronchoconstriction.

Figure 2 Changes in exhaled breath condensate pH. Following exercise, exhaled breath condensate (EBC) pH decreased in the exercise-induced bronchoconstriction (EIB)-positive group (N = 13)) without any change in healthy (P = 0.88, (P = 0.01, ( N = 16)) or EIB-negative (P = 0.51, (N = 9)) individuals. Data are plotted as percentage changes of the pre-exercise value (100%) and expressed as mean ± standard mean of error.

Figure 4 Changes of volatile compound pattern assessed by principal component 3. Exercise caused significant changes in , healthy (N = 16); , exercise-induced bronall groups ( , EIB-negative (N = 9): choconstriction (EIB)-positive (N = 13); all P < 0.05) However, no difference was observed between the groups (P > 0.05). Data are expressed as mean ± standard mean of error.

difference was significant at 0 and 20-min postexercise in healthy subjects and at 10 and 30-min post-exercise in asthmatics compared with preexercise (P < 0.05). However, there was no difference in exhaled volatile compound pattern changes between EIB-positive and EIB-negative subgroups (P = 0.81, Fig. 4). Respiratory droplet dilution did not change in any group (P > 0.05, Fig. 5). The changes in EBC pH were not related to changes in EBC dilution or exhaled volatile pattern (P > 0.05).

DISCUSSION Figure 3 Relationship between changes in exhaled breath condensate pH and lung function. Areas under the time-forced expiratory volume in 1 s (FEV1) curve are plotted against areas under the time-exhaled breath condensate (EBC) pH curve. Bronchoconstriction resulted in lower FEV1 values thus smaller FEV1 areas under the curves (AUC). The smaller FEV1 AUC were correlated with smaller EBC pH AUC, thus lower EBC pH values (P = 0.01, r = 0.68).

Respirology (2014) 19, 563–569

We investigated the changes in EBC pH, a surrogate marker of airway acidity during exercise. A decrease in EBC pH was associated with the development of EIB and was related to the degree of airway narrowing. EBC pH changes were not caused by altered production of airway volatiles or alterations in respiratory droplet dilution, suggesting they resulted from acute changes in airway pH. Breathlessness following physical exercise is a common complaint among asthmatics; however, less © 2014 The Authors Respirology © 2014 Asian Pacific Society of Respirology

EBC pH in exercise-induced bronchospasm

Figure 5 Changes in exhaled breath condensate dilution. Exercise did not change exhaled breath condensate (EBC) dilu, healthy (N = 16); tion significantly in any group (P > 0.05). , exercise-induced bronchoconstriction (EIB)-positive , EIB-negative groups (N = 9). Data are expressed as (N = 13); median ± inter-quartiles range.

than a half of the patients who experience symptoms, develop bronchoconstriction during a standardized physical test.24 In addition, the repeatability of a positive exercise test is also moderate.25 This was supported in the current study, as only 59% of asthmatics had positive exercise challenge test. Notably, exercise challenge was performed at room air and changes in conditions of inhaled air (cold, dry air) might have increased the sensitivity of exercise challenge.26 The possible effect of these conditions on EBC pH is still unclear. To reduce bias resulting from different asthma subtypes, we recruited asthmatic subjects with a previous history of EIB. Nonetheless, the study group was still heterogeneous in other aspects, as seven subjects had negative skin prick test. Therefore, it is not surprising that contrarily to our previous study,13 we could not find higher FENO levels at pre-exercise in EIB, which has a positive predictive value only in atopic subjects.27 However, our results are in concordance with previous studies that showed no difference in preexercise FEV1 between EIB-positive and negative groups.5,13 Although, asthmatics had diverse asthma control, supporting the previous studies,28–30 asthma control was not related to EIB. The exact pathology of EIB is still unclear. Airways lose water during exercise. This effect might have been reflected by increased EBC volume measured immediately after exercise in all subjects in this study. Water loss with parallel impairment of airway ion and water regulation in EIB leads to increased airway osmolarity following exercise.2 Increased extracellular osmolarity elevates intracellular ion concentration and results in a subsequent mediator release by inflammatory cells.31 As airway pH regulation is strongly interrelated with the ion-regulation,6 decrease in airway pH may contribute to these changes; however, this was the first study to investigate this effect. The role of reduced airway pH in EIB is supported by several lines of evidence. Epithelial cell injury © 2014 The Authors Respirology © 2014 Asian Pacific Society of Respirology

567 shown in EIB-positive versus EIB-negative subjects4 may result not only in damaged ion but also in acid–base regulation in the bronchi. Furthermore, increased airway osmolarity may induce airway acidification, as it was shown that hypertonic saline inhalation causes EBC pH decrease.32 In addition, reduced airway pH may directly lead to bronchoconstriction.33 Decreasing pH of the hypertonic saline solution increases the sensitivity for a positive bronchial hyperresponsiveness.34 Pharmacological studies also support the role of airway acidification in EIB, as carbonic anhydrase enzyme inhibitors, such as furosemide35 or acetazolamide36 prevent the development of hyperpnoea-associated bronchoconstriction. We found that the decrease in EBC pH is related to the development and severity of EIB, supporting the causal role of airway pH in exercise-induced bronchoconstricition. Of note, it was previously shown that methacholine-induced bronchoconstriction does not change EBC pH itself.37 EBC pH analysis is a method to assess short-term temporal changes in airway acidity. However, its value is affected by additional factors that limit its use. Volatile acids and bases released throughout the respiratory tract may dissolve in the condensate fluid altering its pH.8 A prominent volatile substance is the mainly orally produced ammonia, which may influence EBC pH.38 Exhaled ammonia increases after exercise in healthy subjects with parallel alkalization of EBC fluid.10 However, it is unlikely that the EBC pH decrease observed exclusively in the EIB-positive group was related to the different production of oral ammonia in EIB. Changes in exhaled volatile compounds may be followed with an electronic nose.8 Electronic noses are composites of nanosensor arrays and a built-in processor with different learning algorithms. The instrument applied in the current study uses carbon black-polymer sensors, which are sensitive for polar compounds such as alcohols, organic acids and esters.39 Numerous polar volatile molecules including isoprene, acetone,40 propionic acid10 or pentane41 alter during exercise and might explain our electronic nose results. Similarly, to healthy subjects,8 we found alterations in exhaled volatile compound pattern during exercise in asthmatics as well. As there was no difference between the EIB-positive and EIB-negative groups, it is not plausible that the EBC pH decrease in EIB was due to modified volatile compound production. Interestingly, contrarily to previous electronic nose studies42,43 there was no difference between asthmatic and healthy subjects before exercise. However, this study was not powered to find these differences. EBC pH is influenced by respiratory droplet dilution.15 To avoid this error we performed dilution estimation using conductivity measurement of vacuum evaporated samples. This technique was used in numerous studies; however, those results may not be directly extrapolated to the similar method, in which dilution is measured in lyophilized samples.15 We did not find differences in respiratory droplet dilution after exercise in any group, which suggests that the EBC pH changes were not due to this factor. Contrarily to some previous studies, we could not find any change in EBC pH of healthy subjects Respirology (2014) 19, 563–569

568 following exercise. A possible explanation for discrepancies could be that exercise-related pH alterations may be work-load dependent44 and physiological EBC pH increase may be blunted in some subjects who reach aerobic/anaerobic threshold during exercise resulting in increased EBC lactate and corresponding EBC acidification.45 In summary, this study investigated the changes of EBC pH during EIB in asthma, and found an association in condensate pH decrease and development of exercise-induced airway narrowing. EBC pH changes may reflect decrease in airway pH, which is supported by the evidence of previous pharmaceutical studies. On the other hand, exercise-induced changes in exhaled biomarkers may also suggest important methodological considerations to avoid physical exercise before performing exhaled breath tests.

Acknowledgements This study was supported by the Hungarian National Research Fund (OTKA 68808) and Hungarian Respiratory Society Research Grant (to Andras Bikov). The authors would like to thank the contribution of Zsofia Koller for the recruitment of subjects.

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© 2014 The Authors Respirology © 2014 Asian Pacific Society of Respirology

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Respirology (2014) 19, 563–569

Exhaled breath condensate pH decreases during exercise-induced bronchoconstriction.

Exercise-induced bronchoconstriction (EIB) is the temporary narrowing of the airways caused by physical exercise. Its exact pathophysiology is unclear...
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