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Cough associated with upper respiratory tract disorders is a common and troublesome problem in children and little is known about the etiology of this type of cough. This study examined the capsaicin cough sensitivity (CS) in children suffering from allergic rhinitis (AR) and upper respiratory tract infection (URI), comparing it with that in healthy children taken as controls (C). CS to capsaicin, spirometry, skin prick tests, and nose-throat examination were performed in 61 children grouped by the diagnosis of AR, URI, and C. The results, in order of C vs. AR vs. URI, expressed as a geometric mean (±95% CI) log10 µM of capsaicin for C2 (the lowest concentration of capsaicin in µmol/l required to induce 2 coughs) were: 1.8 (1.6-1.9) vs. 1.0 (0.8-1.2) vs. 0.48 (0.2-0.8), P<0.001 and for C5 (the lowest concentration of capsaicin in µmol/l required to induce 5 coughs) 2.9 (2.8-2.9) vs. 2.6 (2.5-2.6) vs. 2.1 (2.0 –2.3), P<0.05. We found that CS in children with AR, even when tested out of pollen season, was significantly heightened compared with controls. CS in children with URI was extremely high compared with both C and AR groups. We conclude that pathological processes in the nose of any etiology could cause a sensitization of the cough reflex with decreased cough threshold during asymptomatic period of AR. Cough also is enhanced by acute inflammation in the upper airways in nonatopic children.
Allergic rhinitis is a common cause of chronic cough. Topical corticosteroids are regarded as the most effective first-time treatment in allergic rhinitis. In this study we evaluated the cough sensitivity during the early and late allergic responses in guinea pigs with experimental allergic rhinitis. Another aim of the study was to follow up the effect of inhaled beclomethasone dipropionate on the cough in guinea pigs with allergic rhinitis. 31 guinea pigs were sensitized with ovalbumin (OA). Animals were intranasally challenged with OA (experiment) or saline (control) in 7-day intervals for 9 weeks. Cough was induced by inhalation of citric acid aerosols in gradually increasing concentrations for 30 s and was evaluated 1 h after the 8th nasal challenge (NCH) and 17 h after the 9th NCH. Cough was significantly increased only during an early allergic response, 1 h after repeated NCH [18 (14-23) vs. 8 (3-10); P<0.001]. Five experimental animals were inhaling aerosol of beclomethasone dipropionate seven days between the 8th and the 9th NCH and cough was evaluated 1 h after the 9th NCH. Inhaled corticosteroids significantly inhibited the enhanced allergic rhinitis related cough [4 (1-9) vs.19 (9-37) vs. 6 (3-9); P<0.05].
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Rhinosinusitis is the most common cause of chronic cough. There is clinical experience that cough can be elicited from lower airways including the larynx. However, there is no experimental evidence, that afferent nerve endings localized in the nose or sinuses can directly mediate the cough reflex. Stimulation of nasal afferents affects breathing pattern (apnea) and bronchial smooth muscles (nasobronchial reflex). The question arises of whether stimulation of nasal afferents could also interfere with the cough reflex. Intranasal capsaicin enhances the cough response in cats and guinea pigs. In the present study we address the problem of modulation of the cough response by intranasal capsaicin challenge in humans. Twelve healthy volunteers were recruited for the study. The effect of intranasal capsaicin (25µl, 750µM) and the airway cough threshold were determined at the start of the experiment. After that, cough response was provoked by inhalation of a tussigen during stimulation of nasal afferents with capsaicin and in control conditions in a randomized order. The cough response provoked during intranasal capsaicin was significantly enhanced compared with that during control conditions. Thus, the result was similar to that obtained in previous animal studies. The enhancement of the cough response could be explained by a facilitating interaction between the afferent information of nasal origin and the central neuronal network responsible for creation of cough pattern.
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In the present study we investigated the effects of nasal histamine on the intensity of coughing and the effects of intensified nasal breathing following nasal histamine on cough sensitivity (CS) in 14 subjects with seasonal allergic rhinitis. The study consisted of two parts performed one week apart. First, baseline CS to capsaicin was determined, followed by intranasal histamine challenge (4mg/ml, 0.1 ml) and the count of the number of coughs to inhaled capsaicin on the background of most intensive nasal symptoms (sneezing, itching, rhinorrhea, and nasal blockage) evoked by histamine. In the second part, CS was determined after intranasal histamine followed by 10 min of intensified nasal breathing through the nose or mouth in a randomized order at 2-day intervals. The number of coughs induced after intranasal histamine was significantly higher, compared with intranasal saline, [9 (7-12) vs. 4.5 (4-6), P<0.001]. CS also was significantly increased after nasal histamine, but nasal intensified breathing failed to cause any changes in CS. We conclude that stimulation of nasal mucosa with histamine enhanced the cough response in subjects with allergic rhinitis.
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Reliability of the capsaicin cough reflex sensitivity test in healthy children

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Testing cough reflex sensitivity (CRS) in children requires suitable methodology. A CRS test performed under control of inspiratory flow rate (IFR) shows excellent reliability in children, but it is difficult to perform, especially in younger children. The aim of the present study was to find whether the capsaicin CRS test performed without direct control of constant IFR in healthy children is reliable enough for practical use. The CRS test was performed in 27 healthy children, aged 7-17 yr three times within 8 days. Cough was induced by inhalation of capsaicin aerosol in doubling concentrations (0.61-1250 µmol/l) for 400 ms each. CRS was defined as the lowest capsaicin concentration that evoked 2 or more coughs (C2). Although the intraclass correlation coefficient values showed good to excellent reliability of this test, the within-subject standard deviation values revealed lower reliability of this method compared to the CRS test performed under control of IFR. From the results obtained it is reasonable to conclude that the method using uncontrolled IFR in CRS testing provides acceptable precision only when a bigger sample size is used or more tests are performed. Good to excellent reliability of this method was found in children with higher values of C2 and in those aged 13-17 yr.
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Antileukotriene treatment and allergic rhinitis-related cough in guinea pigs

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Experimental allergic rhinitis produces enhanced cough response in awake guinea pigs. Leukotriene receptor antagonists, as anti-inflammatory agents, have been effective in treatment of asthma and allergic rhinitis to inhibit the early and late allergic response. In the present study, we evaluated the effect of montelukast (Singulair, Merck, USA) on the cough reflex in an experimental model of allergen-induced rhinitis in guinea pigs. Guinea pigs (n=16) were sensitized with intraperitoneal ovalbumin (OVA). The animals were then used to develop a model of allergic rhinitis by repeated intranasal instillation of 0.5% OVA at weekly intervals for 8 weeks. Allergic rhinitis was evaluated from the occurrence of typical clinical symptoms including sneezing, conjuctival and nasal secretion, or nasal acoustic phenomenon. Between the 6th and 8th nasal challenge (NCh) the animals (n=8) were treated daily for 14 days with oral montelukast (10mg/kg). Cough was induced by citric acid aerosol inhalation in gradually increasing concentration (0.05-1.6 M) and was evaluated before sensitization and then after the 1st, 6th, and 8th nasal challenge when rhinitic symptoms were most conspicuous. The intensity of cough was significantly increased after the first and repeated nasal OVA challenges, and reduced after the 8th NCh that was preceded with montelukast treatment [9(6-14) vs. 16.5(14-22) vs. 25.5(23-42) vs. 8.5(8-13); P=0.0003]. We conclude that antileukotriene therapy suppresses the stimulating effect of experimental allergic rhinitis on the chemically-induced cough in awake guinea pigs.
In the present study we investigated the possibility of central convergence of neural pathways coming from distant anatomical regions in modulating the cough response. We addressed this issue by inducing cough from the tracheo-bronchial region on the background of capsaicin-stimulated and mesocain-blocked nasal mucosa in 14 anesthetized guinea pigs. The control group consisted of 6 guinea pigs in which the active agents, capsaicin and mesocain, were substituted for by inert physiological saline. All animals were tracheostomized, and the larynx was disconnected from the proximal part of the trachea with preserved innervations, and all were subjected to the same protocol. Cough, induced by mechanical irritation of the tracheo-bronchial mucosa, was elicited three times: in the control condition, after intranasal capsaicin challenge, and after another capsaicin challenge preceded by intranasal instillation of a local anesthetic, mesocain. The main finding of the study was that the number of cough efforts per bout, assessed from positive deflections on the intrapleural pressure recordings, was significantly enhanced by intranasal capsaicin challenge and this effect was reversed by intranasal pretreatment with the anesthetic mesocain [2.1 ±0.2 (control) vs. 3.5 ±0.4 (capsaicin) vs. 2.2 ±0.2 (capsaicin after mesocain) (P<0.01)], with no appreciable changes in the magnitude of cough efforts. The cough response in the control group remained unchanged. We conclude that tracheo-bronchial cough may be modified by neural sensory input to the brain coming from nasal mucosa. Therefore, cough reflex is subject to central convergence of peripheral neural pathways originating at distant anatomical locations.
Inhalation of high concentration of oxygen produces oxidative stress in men and experimental animals. Our previous experiments showed that the cough reflex is suppressed in guinea pigs after exposure to 100% O2 for 60 hours. The aim of this study was to determine the effects of dietary antioxidant supplementation with vitamins C and E on hyperoxia-induced oxidative stress in airway and lung tissues directed on cough reflex. The experimental group (T-H, n=8) was pretreated with vitamins C (500 mg/kg) and E (300 mg/kg) for 4 weeks and subsequently exposed to 100% O2 for 60 hours. Hyperoxic group (H, n=8) received saline instead of antioxidants and then inhaled 100% O2 for 60 hours. Cough was induced by inhalation of citric acid aerosol in gradually increased concentration (0.05-1.6 M) at the end of antioxidant therapy and then at the end of exposure to 100% O2. Cough was also induced by mechanical stimulation of laryngopharyngeal (LPh) and tracheobronchial (TBr) region in anaesthetized animals just 1 hour after the end of oxygen exposure. Our results showed a tendency to a decrease in citric acid-induced cough in hyperoxic animals and an increase in animals with antioxidant therapy after hyperoxia. Antioxidant therapy significantly unblocked hyperoxia-induced down-regulation of cough (P=0.004). Significant changes also were obtained from mechanically-induced TBr cough [2.5(1-4) vs. 1.0(1-2); P<0.01] between the experimental and hyperoxic (control) animals. In conclusion, our results indicate a protective effect of antioxidant supplementation on oxidant-mediated cough depression.
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