International Journal of Pediatric Otorhinolaryngology (2008) 72, 1717—1722

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Sulphurous water inhalations in the prophylaxis of recurrent upper respiratory tract infections Angelo Salami, Massimo Dellepiane, Barbara Crippa, Francesco Mora, Luca Guastini, Barbara Jankowska, Renzo Mora * ENT Department, University of Genoa, Via dei Mille 11/9, 16147, Genoa, Italy Received 7 July 2008; received in revised form 18 August 2008; accepted 20 August 2008 Available online 24 September 2008

KEYWORDS Children; Recurrent upper respiratory tract infectious; Sulphurous water

Summary Objective: The aim of this study was to evaluate the efficacy and the effect of sulphurous thermal water inhalations in the treatment of the recurrent upper respiratory tract (RURT) infections in children. Methods: A total of 100 children with RURT infections were included. All children underwent a 12-day course warm vapour inhalations. For the inhalations, we used sulphurous thermal water in the group A, while physiological solution in the group B. At the beginning, at the end and 3 months after start, all children underwent medical history, ENT examination, plasma levels of immunoglobulins class E, G, A, M (IgE, IgG, IgA, IgM), subjective assessment of symptoms (VAS), nasal mucociliar transport time (NMTT) determination, and evaluation of frequency, duration, severity and social impact of RURT episodes. Results: Compared with group B, after the treatment and at the end of the study, in children treated with sulphurous thermal water, the serum concentration of IgE was significantly ( p < 0.05) lower (75.13  27.1 mg/dl vs 96.87  41.3 mg/dl; 74.23  26.2 mg/dl vs 98.24  42.7 mg/dl), IgA titers were higher (238.14  122.1 mg/dl vs 218.62  115.8 mg/dl; 239.72  119.7 mg/dl vs 210.46  107.3 mg/dl), serum concentrations of IgG and IgM unchanged, VAS scores presented a significant ( p < 0.05) improvement (1.8  0.19 vs 6.8  0.54; 1.9  0.21 vs 6.9  0.61), NMTT was normal (11.15  1.59 min vs 17.63  2.17; 11.25  2.10 min vs 17.77  2.19 min) and frequency, duration, severity and social impact of RURT episodes were significantly ( p < 0.05) lower. Conclusions: Our findings indicate that, in addition to their known effects, the sulphurous water also have an immunomodulant activity that contributes to their therapeutic effects. # 2008 Elsevier Ireland Ltd. All rights reserved.

* Corresponding author. Tel.: +39 0103537631; fax: +39 0103537684. E-mail address: [email protected] (R. Mora). 0165-5876/$ — see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2008.08.014

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1. Introduction Recurrent upper respiratory tract (RURT) infections are among the most common problems encountered in paediatric practice: they initially occur as a viral respiratory tract infection, but bacterial growth is demonstrated in 60% of patients with symptoms of an upper respiratory tract infection of at least 10 days duration [1,2]. The bacterial flora that colonize the upper respiratory tract, in health as well as in illness, contain over 600 different strains of aerobic and anaerobic bacteria, that interact in a synergistic or antagonistic fashion. Viral agents can act synergistically with potential bacterial pathogens and normal flora [3]. These interactions can involve sharing of metabolites, exchange of genetic material, and influence of extra-cellular enzymes and other compounds produced by some pathogens on their partners [3]. A proper treatment should provide patients with adequate coverage of aerobic as well as anaerobic pathogens so as to minimize recurrences, enhance eradication, maximize compliance and avoid resistance. At present, children affected by RURT infections are cured by means of antibacterial and symptomatic therapy. Especially in the paediatric age, antibacterial therapy is still the traditional approach [4]. Because of antibiotic resistance increase, attention has been focused on the possibility of alternative approaches [5]. The aim of this study was to evaluate the efficacy of sulphurous thermal water inhalations and to approach the mechanism of their effect in the treatment of the RURT infections in children.

2. Methods This double-blinded study was conducted according to the Revised Declaration of Helsinki and The Good Clinical Practice Guidelines. All procedures were carried out in accordance with the local ethics committee’s protocol. A total of 100 children (55 males and 45 females) aged between 6 and 14 years (9 years old on average) with RURT infections (at least three acute episodes in the last year) were included, between September 2007 and March 2008. The diagnosis of infection was made when at least 2 symptoms or fever (axillary temperature 38 8C), in addition to one other symptom, were present for at least 48 h. The symptoms taken into consideration for diagnostic purposes were: mucopurulent rhinorrhea, stuffy or dripping nose or both, headache, facial pain,

A. Salami et al. sore-throat, cough (dry or productive), otalgia (earache), fever, dyspnoea, and mucopurulent secretion [6]. Children treated with immunostimulant or immunosoppressive agents in the previous 6 months and children with previous adenoidectomy and/or tonsillectomy or affected by anatomic anomalies, other acute infections, allergic rhinitis, congenital immunodeficiencies and bronchopulmonary disease were excluded. After signing an informed consent at the beginning, at the end and 3 months after start, all patients underwent medical history, ENT examination by ENT specialist with pharyngeal swabbing, plasma levels of immunoglobulins class E, G, A, M (IgE, IgG, IgA, IgM), nasal mucociliar transport time (NMTT) determination, and subjective assessment of symptoms by visual analog scale: a standard 10 cm visual analog scale (VAS) ranging from 0 (no symptoms, satisfied with the situation) to 10 (the most severe symptoms, dissatisfying situation) was used to assess the subjective symptoms [7]. NMTT was evaluated by the saccharin test at the beginning, at the end and 3 months after start: saccharin transit time was measured after depositing 15 mg of 2% sodium saccharin behind the anterior margin of the inferior turbinate. The patient was instructed to sit with his head inclined forward at an angle of 108; during the test, the patients had a swallow every 30 s and were avoid blowing the nose. The test was stopped when the saccharin was tasted [8]. Frequency, duration, severity and social impact of upper respiratory tract episodes were also adopted as valid criteria. At each control the following parameters were checked: number of episodes (1, 2 or >2), duration (6 days), fever (yes/no), medical consultation (yes/no), disease frequency (once/twice/>twice per month), ancillary therapy (none/symptomatic only/antibacterials) and absence from school (none/1—3/>4 days). The patients were equally divided at random into two groups (A and B). All children underwent a 12day course warm vapour inhalations (38 8C to 20 cm from patient’s face for 10 min). Inhalations were performed in the ENT Department of the University of Genoa, once a day for 12 consecutive days. In the group A, for the treatment we used sulphurous thermal water warm vapour inhalations from The Tabiano SPA Mineral Water (Tabiano, Parma, Italy); the chemical analysis of thermal water is given in Table 1. We used physiological solution in group B. All the data evaluated by the unpaired t-test and x2 analysis were appropriate; probability values at 2 >2

2 >2

1 2 p < 0.05

Duration (6 days) of episodes of RURT infectious

Sulphurous Placebo

50 50

>6 >6

3—6 >6

4 days)

Sulphurous Placebo

50 50

>4 >4

1—3 1—3

None 1—3 p < 0.05

Medical consultation (yes/no)

Sulphurous Placebo

50 50

Yes Yes

Yes Yes

No No

Different studies show that asthma and allergic diseases, primary immunodeficiencies, chronic adenoiditis and tonsillitis, environmental conditions, smoking parents and anatomic-obstructive factors, as well as nutritional zinc and iron deficiencies are the major causes underlying RURT infections in children [10]. Defects in the immune systems are well known to be linked with frequent respiratory tract infections. It has been shown that more than the 50% of children with recurrent RURT infections (at least three episodes a year during at least 2 years) are deficient in one of the IgG subclasses and that at least a third are IgA deficient. IgG subclass deficiency is quite prominent in young children but rare in older children, suggesting a transient immaturity of the immune system as one of the possible pathogenic factors. Defects in the immune system, such as common variable immunodeficiency and the more frequent selective IgA deficiency, are known to be linked with frequent RURT infections caused by bacteria and viruses [11]. At present, there is not a standard treatment for RURT infections. Antibacterial and antiviral chemoprophylaxis are only exceptionally appropriate. The benefit is modest and the risk of selective pressure

of the antibacterial drug for emergence of resistant pathogens is real. Also the efficacy of surgery is unclear: many trials and reviews attempted to define the role of ear, nose and throat surgery (e.g. tonsillectomy, adenoidectomy, myringotomy with/without placement of tympanostomy tubes) in the prevention of RURT infections with poor results [11,12]. With the emergence of resistant strains and the change in the distribution of bacterial flora over the time, preventive strategies such as sulphurous thermal water inhalations may represent a valid alternative approach. Data in the literature have demonstrated the therapeutic effects of mineral waters depending on their physical and chemical properties. The Tabiano water originates is cold-source, highly mineralised (sulphate—calcium—magnesium type) with a high bicarbonate (about 600 mg/l) and a very high hydrogen sulphide content. It is a sulphurous— sulphate—calcium—magnesium water with one of the highest level of sulphur in the world. The natural balance between gases (hydrogen sulphide) and substances (sulphates, bicarbonates, calcium and magnesium) explains its general and local properties (Table 1).

Sulphurous water inhalations in children Studies on the therapeutic effects of sulphurous waters on aspecific inflammation of the upper respiratory tract show a decreased bacterial layer, normalized mucociliary transport, increased lipoprotein metabolism and increased plasma levels of immunoglobulins [13—19]. This water has antibacterial effects: only few microorganisms can survive in a sulphurous water because of the toxicity of sulphide [13]. Mucociliary function represents the first barrier of the upper respiratory tract mucosa against various biological and physical insults. Our results confirm that sulphurous thermal water allows the improvement of mucociliary function, as confirmed by a significant reduction of mean mucociliary transport time: this function commonly prevents organic, inorganic, bacterial or viral particles from entering the organism [14]. Literature reports have demonstrated that this type of water has a very good hypocholesterolaemic activity, because it is able to decrease the lowdensity lipoprotein level in blood through a mechanism of increased excretion of faecal bile acid sterols [15]. A recent study highlights that recurrent episodes of acute respiratory infections could influence vascular phenotypes for early atherosclerosis in children and adolescents with type 1 diabetes, for this reason the hypocholesterolaemic activity may be a useful effect [16]. Recent findings indicate a trophic effects on respiratory mucosa and a mucolytic activity. The sulphurous water has antioxidant activity that contributes to the therapeutic effects of the water in upper airway inflammatory diseases: the inhalation of sulphurous thermal water can modulate its antioxidant activities of the sulfhydryl or thiolic group in the cysteine of glutathione or various low-weight soluble molecules [17]. In chronic inflammatory processes characterized by mucus of the upper respiratory tract, thermal therapy with sulphur mineral water induce beneficial effects on secretions. The sulphurous water acts on the mucoproteins to open disulphide bonds and, consequently lower the viscosity of the mucus [18]. Modulation of the immune system by sulphurous water has been highlighted by different reports [18,19]: in vitro studies have shown that sulphurous thermal water can inhibit the proliferation of normal lymphocytes and T cells obtained from patients with chronic immunomediated diseases. Also, it was reported that sulphurous thermal waters can inhibit interleukin 2 (IL-2) and interferon (INF) gamma release from T helper (TH) 1 lymphocytes, suggesting that sulphurous water inhalation can modulate some physiopathological aspects of the memory T lymphocyte cells. It is known that INF gamma and IL-

1721 2 are the cytokine firstly activate with the consequent induction of other proinflammatory mediators [19—21]. The increased defences by enhancing the endothelial reticulocite system in synergism with the production of IgA show the anti-inflammatory effect of this thermal water [20]. After sulphurous water inhalation, the higher serum concentration of IgA can be attributed to increased production of this immunoglobulin since sulphur supports the assembly of the polypeptide chain. The decreased serum concentration of IgE confirms as the inhalation with sulphurous water can provide beneficial effects in chronic inflammatory disorders by inhibiting the immune response at a local level and cleaning the respiratory mucosa from the irritians [19—21]. Efficacy of inhalation depends on various factors influencing particles deposition in the airways, such as type of adopted nebuliser, particles’ size, airways calibre and patient’s breathing pattern. The nebuliser able to produce particle with a diameter lesser than 3 mm can reach the smaller bronchioli. The vapour penetration in the respiratory tissues determines a marked osmotic action that allows the water to cleanse the mucous epithelium and avoids the irritants to enhance seric IgE production by activation of cytokine, chemokine, macrophages: the absence of this stimulation causes a lymphocytes TH1 polarization and the end of TH2-driven allergic response [20,22]. It has also been reported that the analgesic effect of the sulphurous water appears to be related to a neuroendocrine activation, promoting an increase of seric levels of opioids peptides, such as endorphins and encephalins [22]. Our findings indicate that, in addition to their known mucolytic activity, trophic and antioxidant effects on respiratory mucosa, the sulphurous water also have an immunomodulant activity that contributes to the therapeutic effects of the water in upper airway inflammatory diseases. For these reasons, thermal treatment could represent the first alternative choice to drugs in chronic, nonresponsive inflammatory diseases. The results of this study are in agreement with data in the literature, demonstrating that inhalation of sulphurous water have a positive impact on the therapeutic strategy of RURT inflammatory processes.

Conflict of interest statement All authors have not any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work.

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