The treatment of diseases with thermal water belongs to the oldest medical therapies. Waters and their components were used as therapeutic agents from the nineteenth century to the present day especially for lung diseases. The most frequently used therapies based on mineral waters were drinking, bath, and inhalation cures. The positive influence of these cures on the recovery of the patients was attributed to the physicochemical properties of the water. Particulary, some studies show that sulphurous thermal water inhalation has mucolitic, antioxidant, and antielastase activity [
The design of the present study was focused on two groups of patients with pneumoconiosis and with bronchial diseases inhaling salt-bromide-iodine thermal water in Terme of Monticelli (Parma), Italy. This thermal water is classified as medium-mineral and contains bromide, iodide, hydrogen sulphide, and sulphates, springs forth at temperature of 13°C, and is used in treatment of different respiratory diseases. The aerosol was administrated daily for 12 consecutive days. Spirometry and exhaled breath collection was performed before and after 12 days of treatment. Subjects completed also a questionnaire covering respiratory symptoms, smoking habits, and information about environmental and occupational exposures.
The protocol was approved by the Ethic Committee of the University Hospital of Parma, and patients signed an informed consent.
This study enrolled two groups, twenty (20) patients with alveolar pulmonary diseases—pneumoconiosis—(15 men and 5 women, aged 54–84) and twenty two (22) patients with bronchial diseases (11 men and 11 women, aged 41–82). Patients received 12 days inhalation treatment with salt-bromide-iodine water in Terme of Monticelli (Parma), Italy. The pneumopathology of each subject was ascertained according to standard diagnostic tests with the recommendations of the American Thoracic Society/European Respiratory Society (ATS/ERS) [
Characteristic of the groups.
Subjects | Gender | Age | BMI | Smokers/Ex-smokers ( |
Pack/years (PY) |
---|---|---|---|---|---|
Total ( |
M = 26; F = 16 |
|
|
7/18 | 23.5 (14.3–39.5) |
| |||||
Alveolar diseases ( |
|||||
(i) Silicosis ( |
M = 10; F = 2 |
|
|
0/8 | 17 (5.8–37.3) |
(ii) Asbestosis ( |
M = 3; F = 3 |
|
|
2/1 | 24 (1.4–68) |
(iii) Silicoasbestosis ( |
M = 2; F = 0 |
|
|
0/1 | — |
| |||||
Bronchial diseases ( |
|||||
(i) Chronic bronchitis ( |
M = 7; F = 8 |
|
|
3/6 | 22.5 (14.5–70.3) |
(ii) Asthma ( |
M = 4; F = 3 |
|
|
2/3 | 23.4 (17.1–50.5) |
Smokers or ex smokers with PY > 10 ( |
M = 17; F = 4 |
|
|
7/14 | 25 (17–48.8) |
Data presented as mean ± SD; SD: standard deviation or median (IQR); IQR: interquartile range.
Forced vital capacity (FVC), forced expiratory volume (FEV1), FEV1/FVC ratio, peak expiratory flow rate (PEFR), and forced expiratory flow 25–75% (FEF 25–75%) were measured using a KOKO spirometer (Sensormedics Italia Srl, Milan, Italy), and the best of three values were expressed as a percentage of the predicted normal value. Measurements were obtained and evaluated in accordance with the recommendations of the ATS/ERS [
eNO was measured by portable device composed with electrochemical sensor (HypAir FENO, Sensormedics, Milan, Italy). The analyzer was calibrated by the manufacturer with range from 100 to 1000 ppb, linearity error < 0.5%, and reproducibility of ±2.5 ppb adapted for online recording of NO concentration in exhaled breath. HypAir FENO is enabled to measure the eNO at multiple exhaled flow rates and calculates bronchial and alveolar eNO concentration. It is possible to calculate also three flow-dependent NO exchange parameters: airway tissue nitric oxide concentration (
The transportable unit TURBO-DECCS condenser (Medivac, Parma, Italy) was used for EBC collection. Patients were asked to breath tidally through the mouthpiece for 15 minutes through a two-way non-rebreathing valve by which inspiratory and expiratory air is separated and saliva is trapped. The temperature of the condenser was set at −5°C, respecting all of the recommended practical standards and anticontamination principles for EBC collection published by ATS/ERS [
H2O2 in EBC was measured using a commercial kit (Amplex Red Hydrogen Peroxide/Peroxidase assay kit, Molecular Probes, Eugene, OR, USA). Briefly, 50
EBC samples were sent, on dry ice, to the Laboratory of Industrial Hygiene and Toxicology, University Hospital of Brescia (Italy). The laboratory is certified for analysis of metallic elements. EBC samples underwent inductively coupled plasma-mass spectrometry (ICP-MS) analysis on a Perkin Elmer ELAN DRC II instrument (Perkin Elmer, Sciex, Canada) using an analytical technique for total quantification with external calibration and reference material. For each sample, two runs were performed (two replicates each), one with dynamic reaction cell (DRC) and one without DRC. We determined concentrations of the following elements: arsenic (As), barium (Ba), cadmium (Cd), calcium (Ca), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), mercury (Hg), manganese (Mn), molybdenum (Mo), nickel (Ni), lead (Pb), selenium (Se), strontium (Sr), tin (Sn), vanadium (V), and zinc (Zn); Cr and Fe were determined by DRC using NH3 at a flow of 0.6 mL/min. The method accuracy was determined in natural water standard reference materials (NIST 1640 from the National Institute of Standard and Technology, Gaithersburg, MD 20899-1070). The coefficients of variation (CV) ranged from 4% to 8% among series and from 6% to 12% between series. The instrument was calibrated using standard solution at a concentration of 10
The quantification of anions was performed by ion exchange Dionex chromatography (ICS 2100, Dionex Corporation, Sunnyvale, CA). One hundred
The data were statistically analyzed using the SPSS software v.17.0 (SPSS inc., Chicago, IL, USA) and a
The EBC anion concentrations were compared before and after inhalation of thermal salt-bromide-iodine water in the group of patients with pneumopathologies and
Twenty patients with occupational pneumoconiosis and twenty-two with bronchial diseases (asthma and chronic bronchitis) were examined. Among 42 recruited subjects, 7 current smokers and 18 ex-smokers with PY of 23.5 (14.3–39.5) were present, and subgroup of 21 patients with relevant smoking history (at least 10 PY) and PY of 25 (17–48.8) was distinguished. In 14 subjects, the airflow obstruction as ratio between FEV1/FVC (<0.7) was found; the obstruction was present in six patients with bronchial diseases and in eight patients with alveolar diseases. Among the patients with airway obstruction, two subjects were current smokers, eight of them were ex-smokers and four patients were never smokers.
Table
Effect of 12 days thermal treatment with salt-bromide-iodine thermal water on lung function parameters.
Variables | Alveolar diseases | Bronchial diseases | ||||
---|---|---|---|---|---|---|
BT | AT |
|
BT | AT |
| |
FVC (L) |
|
|
ns |
|
|
ns |
FEV1 (L) |
|
|
ns |
|
|
ns |
FEV1/FVC (L) |
|
|
ns |
|
|
ns |
PEFR (L/s) |
|
|
ns |
|
|
|
|
|
|
ns |
|
|
ns |
Data expressed as mean ± SD; SD: standard deviation; *Paired
Effect of 12 days thermal treatment with salt-bromide-iodine thermal water on lung function parameters in patients with airflow obstruction (FEV1/FVC < 0.7).
Variables | Treatment |
| |
---|---|---|---|
BT | AT | ||
FVC (L) |
|
|
ns |
FEV1 (L) |
|
|
ns |
FEV1/FVC (L) |
|
|
|
PEFR (L/s) |
|
|
ns |
|
|
|
ns |
Data expressed as mean ± SD (standard deviation); *Paired
There were no significant differences for levels of FENO at different flow rates (50, 100, 150, 350) in both groups of patients before and after thermal salt-bromide-iodine water inhalation, as reported in Table
Effect of 12 days treatment with salt-bromide-iodine thermal water on flow-dependent NO parameters (FENO50, FENO100, FENO150, FENO350,
Variable | Alveolar diseases | Bronchial diseases | ||||
---|---|---|---|---|---|---|
BT | AT |
|
BT | AT |
| |
FENO50 (ppb) | 25 (13.3–37.8) | 26 (16.7–44.5) | ns | 24 (17–52) | 20 (17–31) | ns |
FENO100 (ppb) | 18 (14–28) | 18.5 (12–22.8) | ns | 17 (12.5–24) | 16 (11–26) | ns |
FENO150 (ppb) | 12 (11.5–23.5) | 11.5 (9.7–23.5) | ns | 15.5 (10–22) | 12.5 (10.5–18.5) | ns |
FENO350 (ppb) | 10 (6.5–10.5) | 9 (5.5–12.8) | ns | ND | ND | ND |
|
54.8 (35.7–112) | 65 (37.8–92.2) | ns | 54.4 (35.8–80.6) | 33.5 (24.0–73.8) | ns |
|
6.6 (3.1–12.2) | 6.2 (4–9.6) | ns | 7.4 (3.4–19.6) | 9.4 (5–15.6) | ns |
Data expressed as median IQR; IQR: interquartile range; #Wilcoxon rank-sum test; BT: before treatment; AT: after treatment; FENO50: fractional nitric oxide concentration at flow rate of 50 mL/s; FENO100: fractional nitric oxide concentration at flow rate of 100 mL/s; FENO150: fractional nitric oxide concentration at flow rate of 150 mL/s; FENO350: fractional nitric oxide concentration at flow rate of 350 mL/s;
In the group of patients with alveolar diseases, the H2O2-EBC concentrations before thermal treatment were not significantly compared after inhalation (0.29 (0.19–0.58)
Effect of 12 days treatment with salt-bromide-iodine thermal water on H2O2-EBC concentrations.
Variable | Alveolar | Bronchial | ||||
---|---|---|---|---|---|---|
BT | AT |
|
BT | AT |
| |
H2O2 ( |
0.29 (0.19–0.58) | 0.28 (0.09–0.9) | ns | 0.29 (0.18–0.58) | 0.34 (0.13–0.91) | ns |
Data expressed as median (IQR); IQR: interquartile range; #Wilcoxon rank sum test; BT: before treatment; AT: after treatment; ns: not significant.
Concentrations of metals quantified before and after treatment in EBC smokers and ex smokers with significant smoking history (PY > 10) are reported in Table
Effect of 12 days treatment with salt-bromide-iodine thermal water on EBC metals concentrations.
Metals | BT (mg/L) | AT (mg/L) |
|
---|---|---|---|
Al | 1.36 (0.73–2.2) | 1.4 (1.1–2.3) | #ns |
Mn | 0.38 (0.28–0.69) | 0.5 (0.32–1.0) | #ns |
Co | 0.02 (0.006–0.06) | 0.02 (0.006–0.1) | #ns |
Sr |
|
|
*ns |
Ba |
|
|
*ns |
Ca | 249 (38.5–394) | 270 (67–348) | #ns |
Pb |
|
|
*ns |
I |
|
|
*ns |
Cu |
|
|
*ns |
Si | 50 (28.8–69.8) | 32 (15–62) | #ns |
Fe | 2.5 (1.2–7.2) | 3.1 (1.5–6.3) | #ns |
Cr |
|
|
*ns |
Ni | 1.0 (0.3–5.8) | 1.0 (0.85–6.1) | #ns |
Rb |
|
|
*ns |
Data expressed as median (IQR); IQR: interquartile range or mean ± SE; SE: standard error; #Wilcoxon rank sum test; *Paired
The concentrations of anions in patients before and after inhalation of salt-bromide-iodine thermal water
EBC anions concentrations (ppb =
Anion | Treatment | Controls | |
---|---|---|---|
BT | AT | ||
Formate |
|
|
|
Chloride |
|
|
|
Nitrite |
|
|
|
Nitrate |
|
|
¥
|
Sulphate |
|
|
|
Oxalate |
|
|
|
Data reported as median values (IQR); IQR: interquartile range, only for nitrate as mean values ± SD (SD: standard deviation); ¥one-way ANOVA analysis of variance with Post Bonferroni test,
EBC nitrate concentrations for patients before and after inhalation of thermal salt-bromide-iodine water
The positive effect of the thermal water inhalation is generally based on the patients’ subjective sense of wellbeing, whereas more difficult is to measure or quantify clinical improvements. In our study, we assessed the effects of salt-bromide iodine thermal water inhalation on lung functions parameters and on effect biomarkers. To the best of our knowledge, this is the first study that has used FENO measurement at multiple exhaled flow rates in exhaled breath, metals, and anions quantification in EBC, in order to investigate the biochemical changes airways in patients with bronchial and alveolar pneumopathologies who receive the inhalation thermal treatment with salt-bromide-iodine water. Most of our patients, who receive thermal treatment every year, have confirmed the subjective improvement and sense of “easier breathing,” which usually appear in the next weeks after the end of the treatment. The PEF value in patients with bronchial diseases have increased significantly (Table
There is no evidence that thermal water inhalation affects the inflammation and oxidative stress in the airways and modify pulmonary concentration of smoking-related biomarkers after 12 days treatment. Probably, the improvement of functional parameters and the modification of exhaled biomarkers are not detectable immediately within 12 days of treatment, and repeated follow-up examination several weeks after the end of thermal water inhalation could be important for a better understanding of possible long term effects.
American Thoracic Society
Airway tissue nitric oxide concentration
Alveolar nitric oxide concentration
Airway transfer factor
Maximum total airway nitric oxide flux
Chronic obstructive pulmonary disease
Exhaled breath condensate
Epithelial lining fluid
European Respiratory Society
Fractional exhaled nitric oxide
Forced expiratory flow 25–75%
Forced expiratory volume
Forced vital capacity
Gluthatione
Horseradish peroxidase
Hydrogen peroxide
Hydrogen sulphide
Interquartile range
Limit of detection
Nitric oxide
Peak expiratory flow rate
Standard deviation.
M. Corradi participated in the design of the study, conducted participant visits, and analysed and interpreted the data. G. Folesani participated in the design of the study, analysed and interpreted the data, and drafted paper. P. Gergelova helped to draft the manuscript. M. Goldoni participated in the design of the study and assisted in interpretation of the data. S. Pinelli assisted with acquisition and interpretation of the data. G. Gainotti participated in the design of the study. G. De Palma participated in the design of the study and assisted with acquisition of the data. A. Mutti participated in the design of the study and helped to draft the paper. All authors have read and approved the final paper.
The authors declared that there is no conflict of interests with any financial organization regarding the material discussed in the paper.
This study was supported by a grant from The Italian Association for Cancer Research (AIRC). Fondazione Ricerca Scientifica Termale (FoRST). The authors thank the staff of the Terme of Monticelli (Parma), Italy. Dionex Italia S.P.A. is gratefully acknowledged.