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Effects of inhalation of thermal water on exhaled breath condensate in chronic obstructive pulmonary disease

Clinical Investigations
Accepted after revision: April 6, 2009 Published online: July 3, 2009 Effects of Inhalation of Thermal Water
on Exhaled Breath Condensate in Chronic
Obstructive Pulmonary Disease

Gabriella Guarnieri a Silvia Ferrazzoni a Maria Cristina Scarpa a Alberto Lalli b a Department of Environmental Medicine and Public Health, University of Padova, and b Centro Studi Termali Pietro d’Abano, Montegrotto Terme-Abano Terme, Padova , Italy Key Words
There is no evidence that TW treatment affects LTB 4 concen- Lung function ؒ Normal saline ؒ Aerosol therapy ؒ tration in EBC. The results of EBC pH measurements suggest Leukotriene B 4 ؒ Pulmonary inflammation that TW inhalation induces an imbalance of volatile compo-nents of the buffer system in airway lining fluid. Abstract
Background: Inhalation of thermal water (TW) is tradition-
ally used as part of the treatment of chronic obstructive pul-
monary disease (COPD), but its benefit and mechanisms are controversial. We previously observed a reduced proportion Chronic obstructive pulmonary disease (COPD) is of neutrophils in induced sputum after treatment with TW. characterized by pulmonary inflammation, progressive Objectives: The aim of this study was to determine whether
airflow limitation not completely reversible, and is often inhalation of TW in COPD patients is associated with bio- associated with symptoms of chronic bronchitis [1] . Man- chemical changes of airway lining fluid, including a reduc- agement of COPD requires the integration of several dif- tion in the neutrophil chemoattractant leukotriene B 4 (LTB 4 ). ferent components: minimizing risk factors, educational Methods: Thirteen COPD patients were randomly assigned
programs, improving symptoms with a stepwise treat- to receive a 2-week course of TW and normal saline inhala- ment approach, preventing exacerbations, rehabilitation, tion in a cross-over, single-blind study design. Exhaled breath oxygen therapy and eventually surgical treatments. Inha- condensate (EBC) was collected before and after treatments. lation of thermal water (TW) is traditionally used as part LTB 4 concentrations in EBC were determined by ELISA, and of the treatment of COPD and chronic bronchitis, but is EBC pH was measured before and after argon deaeration. not included among management options by the most Results: No significant differences in LTB 4 concentrations in
recent guidelines [1] , since its benefit and physiopatho- EBC were detected with either treatment. A significant de- logical mechanisms are not yet well clarified. While TW crease in pH of non-deaerated EBC was observed after a stan- is shown to have some anti-inflammatory properties in dard course of TW (median 7.45, interquartile range 6.93– patients with rhinitis [2] , few investigations were per- 7.66, vs. median 6.99, interquartile range 6.57–7.19; p = 0.05), formed in the lower respiratory tract [3] . We previously which disappeared after argon deaeration. Conclusions:
observed a reduced proportion of neutrophils in induced Dipartimento di Medicina Ambientale e Sanità Pubblica Via Giustiniani 2, IT–35128 Padova (Italy) Tel. +39 049 821 2564, Fax +39 049 821 2566, E-Mail Table 1. Physical/chemical characteristics of TW and normal sa-
clinically significant diseases, exacerbation of COPD or respira- tory infection within the last 4 weeks, and treatment with inhaled or systemic corticosteroids in the previous month. Short- and long-acting ␤ -agonist bronchodilators were permitted during the study. All patients gave written informed consent. The study was approved by the ethics committee of the University Hospital of Padova and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
The subjects were randomly assigned to receive a 2-week course of TW or normal saline inhalation in a cross-over, single- blind study design. The wash-out period between treatments was at least 4 weeks. TW originated from hot springs (approximately at 80 ° C) in the Terme Euganee area (Abano Terme-Montegrotto, Veneto, Italy). The main characteristics of TW compared with normal saline are shown in table 1 . TW and normal saline solu- tion were kept at a temperature of approximately 37 ° C and nebu- lized with an output of 50 ml/min. The aerosols were adminis-tered once a day for 20 min. Each subject was examined before and after each treatment (TW and normal saline), for a total of 4 visits. Each visit included the evaluation of chronic bronchitis symptoms and dyspnea using the Communauté Européenne du sputum after TW treatment, suggesting that TW may charbon et de l’Acier (CECA) questionnaire, pulmonary function have a mild anti-inflammatory effect on the airways [4] . tests and EBC collection. Dyspnea was graded from 0 to 4.
The measurement of markers in exhaled breath conden- To evaluate the acute effect of aerosol inhalation, EBC was col- lected before and after a single 20-min inhalation of normal saline sate (EBC) has been suggested to be a useful and relative- and TW on 2 separated days prior to the 2-week treatments.
ly inexpensive method for assessing and monitoring air-way inflammation [5] . Compared with bronchoalveolar lavage, EBC is noninvasive and does not require instilla- FEV 1 and FVC before and 15 min after inhalation of 200 ␮ g of tion of saline into the lung. Furthermore, it does not in- salbutamol were performed with a pneumotacograph (SpiroAna-lyzer ST-150, Fukuda Sangyo, Japan). The predicted normal val- fluence the percentages of airway inflammatory cells, ob- served in some instances after inhalation of hypertonic saline solution for sputum induction [6] .
The aim of this study was to determine whether in- EBC was collected during oral tidal breathing using a com- haled salt-bromide-iodine TW could modify airway lin- mercial condenser (Turbo Deccs 04, Italchil, Parma, Italy). The subjects were not allowed to eat or drink for at least 1 h before EBC ing fluid in COPD patients. For this purpose, we analyzed collection. They breathed normally through a mouthpiece for 15 EBC pH and concentrations of the neutrophil chemoat- min and a 2-way non-rebreathing valve that also served as a sa- tractant leukotriene B 4 (LTB 4 ) before and after a 2-week liva trap. If the subjects felt saliva in their mouth, they were in-course of TW inhalations using normal saline treatment structed to swallow it. Condensate, at least 1 ml, was collected at as a control, in a cross-over, single-blind study design.
–10 ° C and transferred to 3 Eppendorf tubes. Then, all samples pH was measured using a calibrated pH meter (model pH300, Hanna Instruments, Padova, Italy) with a flat membrane elec- trode (5207, Crison Instruments SA, Alella, Spain) and an accu-racy of 8 0.01. In the ATS/ERS task force, Horváth et al. [8] argues that although many investigators believe that the measurements Thirteen patients (10 men and 3 women, aged 47–83 years) of EBC pH after deaeration is the most validated technique, oth- with COPD, diagnosed according to the Global Initiative for ers consider that gas standardization is unnecessary. For the ac-Chronic Obstructive Lung Disease (GOLD) [1] , were recruited tual divergence of views, we consider of interest to perform the from a local general practice. Eligible patients were current or for- EBC measurements prior to and following argon gas to achieve mer smokers with at least a 5-pack-years smoking history. Ac- gas standardization for 3 min, as reported previously [9] . To rule cording to the GOLD guideline, postbronchodilator forced expi- out contamination of EBC by saliva, amylase concentration in the ratory volume in 1 s (FEV 1 )/forced vital capacity (FVC) ! 70% de- samples was measured using an enzymatic colorimetric test fines the airflow limitation of COPD, and reversibility after (IFCC, Roche Diagnostic Modular, lower limit of detection 3 U/l). inhaled salbutamol (400 ␮ g) must be ! 12% and 200 ml of initial Amylase was undetectable in all of the samples tested.
FEV 1 . Exclusion criteria were atopy and asthma history, other LTB 4 concentrations were measured with specific enzyme im- 7.79, vs. 7.45, IQR 7.34–7.87, respectively) ( fig. 1 a, c). Non- munoassay (Assay Design Inc., Ann Arbor, Mich., USA) with a deaerated EBC pH after 2-week TW inhalations was sig- sensitivity of 5.63 pg/ml. To prevent adherence of fatty acid deri- nificantly decreased (7.45, IQR 6.93–7.66, vs. 6.99, IQR vates (such as leukotrienes), all polypropylene tubes were coated with Tween 20 [10] .
6.57–7.19; p = 0.05) ( fig. 1 b). No significant changes were observed in deaerated EBC pH after TW (before treat- ment 7.58, IQR 7.26–7.71, vs. after treatment 7.24, IQR The values of EBC LTB 4 and pH after a single inhalation of TW and normal saline were regarded as the baseline for the 2-week treatment. Data are expressed as the means 8 standard error (SE) 4 concentration did not significantly change or the median and interquartile ranges (IQR). The Mann-Whit- after both treatments. Similarly, no significant differenc- ney U test was used for comparison between groups, and the Wil- es were detected in lung function and dyspnea score ( ta- coxon rank sum test was used to compare the data before and after treatment. The significance was accepted at the 5% level.
In this study, we showed that a conventional course of The characteristics of the subjects are given in table 2 . inhaled salt-bromide-iodine TW is associated with bio- No COPD exacerbation occurred during the course of chemical changes of airway lining fluid in COPD pa-the study and inhaled treatments were well tolerated. One subject withdrew his consent for personal reasons and did not complete the study.
Median baseline EBC pH was 7.09 (IQR 5.93–7.43) and Table 2. Characteristics of the study subjects
7.29 (IQR 6.27–7.57) before and after argon deaeration(p ! 0.01), respectively.
4 concentration was measurable in the EBC of all subjects. We did not detect any changes in EBC LTB centrations after a single inhalation of either treatments Smoking history, former/current ( table 3 ). Similarly, no acute variations were demonstrat- ed in non-deaerated EBC pH. In contrast, after a single FEV1, % predicted inhalation of normal saline, deaerated EBC pH increased compared with corresponding baseline values (p = 0.01; Stage I (mild), % Figure 1 shows non-deaerated and deaerated EBC pH before and after a 2-week treatment with normal saline Chronic bronchitis, % and TW. No significant effects on non-deaerated and de-aerated EBC pH were observed after normal saline (7.23, Data are expressed as the mean 8 SE. Number in parentheses are percentages. BMI = Body mass index.
IQR 6.66–7.54, vs. 7.30, IQR 6.98–7.49, and 7.47, IQR 7.29– Table 3. Acute effects of a single 20-min inhalation of normal saline and TW on non-deaerated and deaerated EBC pH and LTB4 con-
Data are expressed as the median, with interquartile ranges in parentheses. * p = 0.01 versus before treatment.
Fig. 1. Non-deaerated and deaerated EBC
pH before and after 2-week treatment with normal saline and TW. a Median non-de-
saline solution. b Median non-deaerated
EBC pH before and after TW. c Median de-
saline solution. d Median deaerated EBC
pH before and after TW.
Table 4. EBC LTB4 concentration, FEV1 and dyspnea score before and after 2-week treatment with normal saline and TW
Data are the median with interquartile ranges in parentheses, or the mean 8 SE.
tients. A significant decrease was observed in non-deaer- of LTB 4 data because LTB 4 concentrations in EBC exhib- ated EBC pH after inhalation of TW which disappeared ited high variability.
after argon deaeration. No significant differences in EBC EBC consists mostly of water with trapped aerosolized LTB 4 concentrations were detected either with TW or droplets from the airway lining fluid, as well as of water-with normal saline treatments.
soluble volatile compounds. It is believed that pH of EBC LTB 4 was measurable in EBC at concentrations above is determined largely by the water-soluble volatile gases the detection limit of the immunoassay. EBC LTB 4 levels and reflects, but does not precisely quantitate, that of air- previously found in stable COPD were highly variable, way lining fluid. Several investigators reported that val-ranging between 10 and 100 pg/ml [11–14] . In healthy ues of deaerated EBC pH in healthy subjects range be-subjects, the EBC LTB concentration was higher in tween 7.5 and 8.1 [15] . According to data distribution de- smokers than in nonsmokers (9.4 vs. 6.1 pg/ml) [13] . We scribed by Paget-Brown et al. [16] , pH values ! 7.4 should confirmed that EBC LTB 4 concentrations are elevated in be considered abnormally low. We confirmed that EBC COPD. However, the results do not provide evidence that pH is lower in patients with COPD than in healthy sub- the reduced proportion of neutrophils in induced sputum jects [17–19] . The causes of airway acidification in COPD after TW treatment [4] is due to decreased LTB 4 concen- have not been clarified and could reflect intrinsic airway trations. Caution should be shown in the interpretation acidification induced by altered airway pH homeostasis as a consequence of infections and inflammatory pro- current smokers. It is controversial whether smoking in- cesses [20] or the presence of hypopharyngeal gastric acid creases EBC pH variability and decreases EBC pH. Bor- reflux, which is very common in patients with obstruc- rill et al. [19] ruled out that being a current smoker affects EBC pH in COPD patients. Similar results were previ- A single 20-min inhalation of aerosol tended to in- ously reported by Vaughan et al. [26] . In contrast, Do et crease EBC pH irrespective of whether TW or normal al. [27] observed that acute smoking is associated with a saline is inhaled. This phenomenon was more evident low EBC pH, and asthmatic smokers exhibited more EBC with normal saline after CO 2 removal. In contrast, Car- pagnano et al. [22] were unable to detect pH changes in This study may be underpowered to detect subtle dif- EBC pH after saline inhalation. Probably, the longer time ferences in EBC pH induced by aerosol inhalation in the of inhalation and the larger output of nebulizer in our presence of other sources of variability. In fact, the sam-protocol can explain the discrepancy in the results. We ple size was calculated to show a difference of 2.0 pg/ml predicted that a massive aerosol inhalation could modify in EBC LTB 4 concentration assuming a standard devia- the airway lining fluid pH. For this reason, the effects of tion of 1.8.
inhalation treatments were evaluated after correction for Even though this study was not designed to show clin- the acute changes of EBC pH values after a single 20-min ical and functional effects of TW, we observed some de- crease in dyspnea scores after 2-week TW treatment, but The different chemical composition of TW compared the change was not statistically significant. This result is with normal saline could explain the change in EBC pH. in line with our previous observations that variables re-The finding that the differences in EBC pH were more lated to health perception are more sensitive than func-evident before argon deaeration suggests that TW inhala- tional indexes to detect effects of treatment with TW [4] .
tions may induce an imbalance of volatile components of In conclusion, we have rejected the hypothesis that the buffer systems, NH 4 + /NH 3 and CO 2 /HCO 3 – , involved in reduced proportion of neutrophils in induced sputum af- determining the EBC pH. Talking about a negative effect, ter TW inhalations is due to decreased LTB 4 . We have a proinflammatory effect of TW is probably too strong shown that a conventional treatment with salt-bromide-and certainly does not correspond to what we showed in iodine TW in COPD is associated with some decrease in our previous study.
EBC pH. The results suggest that a chemical composition It has been shown that NH 4 + is the most abundant cat- of TW induced an imbalance of volatile components of ionic buffer in the EBC of healthy subjects and patients buffer systems of airway lining fluid.
with COPD [23, 24] . EBC NH 4 + derives from NH 3 gas re-leased from the saliva especially. Bacterial degradation of urea is responsible for much of the NH 3 generated in the Acknowledgments
mouth. When the mouth is washed with acidic solutions (which tend to trap NH This research was supported by the Fondazione per la Ricerca Scientifica Termale grants, Roma, Italy, by the Centro Studi Ter- can be reduced by 90% [25] . A decrease in ammonia by a mali Pietro d’Abano, by the University of Padova and by Associ- similar washing mechanism due to massive aerosol inha- azione Ricerca Cura Asma, Padova, Italy. The authors thank lation with a consequent reduction in pH due to EBC con- Giovanna Fulgeri and Annabella Gaffo for their secretarial assis- tance, Dr. Roberta Venturini for the amylase assay and Luigi Zed- 2 can be hypothesized. The expected effect has not occurred, but the reduction in EBC pH observed was da for his technical assistance. limited, on average 0.46 and 0.34 prior and following ar-gon deaeration, respectively. It was highlighted that be- References
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