Antonio Foresi

Once daily intranasal fluticasone propionate (200 μg) reduces nasal symptoms and inflammation but also attenuates the increase in bronchial responsiveness during the pollen season in allergic rhinitis

BACKGROUND Fluticasone propionate aqueous nasal spray, a new topical corticosteroid, has been proved to be an effective treatment for seasonal allergic rhinitis. OBJECTIVES We studied the effect of fluticasone propionate on nasal symptoms, circulating eosinophils, and nasal inflammation in patients with seasonal allergic rhinitis after high-load pollen exposure. Moreover, we examined its efficacy in preventing the increase in bronchial responsiveness to methacholine (PD20) during the pollen season. METHODS We conducted a double-blind, placebo-controlled, parallel-group study in patients who had a history of allergic rhinitis in response to pollens of grass and Parietaria species and were living in northern Italy. After a run-in period of 2 weeks, 24 patients were treated with fluticasone propionate (200 micrograms, once daily), and 26 patients received matched placebo for 6 weeks, starting from the beginning of the pollen season. Assessment of efficacy was based on scores of daily nasal symptoms. Nasal lavage was performed at the end of the season, and differential cell count was expressed as percent of total cells. PD20 methacholine was measured at the beginning and end of the season and after the season had ended. RESULTS Fluticasone propionate significantly reduced nasal obstruction, itching, and rhinorrhea. Eosinophils in blood (p < 0.01) and nasal lavage (p < 0.001) were also reduced. Moreover, fluticasone significantly attenuated the decrease in mean PD20 methacholine (from 1.95 to 0.89 mg) compared with placebo (from 1.38 to 0.37 mg: p < 0.01). After the season, no difference in PD20 methacholine was found between treatment groups. CONCLUSIONS The results of this study indicate that fluticasone propionate is effective in decreasing nasal symptoms and eosinophil inflammation in patients with seasonal allergic rhinitis after high-load pollen exposure. Our results also demonstrate that treatment with fluticasone propionate partially prevents the increase in bronchial responsiveness provoked by the inhalation of seasonal pollens in allergic rhinitis.

Eosinophils, mast cells, and basophils in induced sputum from patients with seasonal allergic rhinitis and perennial asthma: Relationship to methacholine responsiveness☆☆☆★

OBJECTIVES We attempted to determine whether inflammation is present in induced sputum of patients with seasonal allergic rhinitis (AR) as compared with those with perennial asthma (AS) and examined its relationship with bronchial responsiveness to methacholine. METHODS Sputum was induced in 30 patients with seasonal rhinitis in response to grass pollens only and in 15 patients with stable, asymptomatic asthma. The AR group was divided according to methacholine PD20 value: the AR- group (n = 15) had a methacholine PD20 greater than 24 micromol; the AR+ group (n = 15) had a methacholine PD20 ranging between 2.2 and 19.6 micromol. In the AS group, methacholine PD20 ranged between 0.42 and 2.6 micromol. The percentage of eosinophils and metachromatic cells (alcian blue-positive) was assessed in sputum by light microscopy. Tryptase-positive cells and EG2+ cells were identified by immunocytochemistry with the mouse anti-human mast cell-tryptase monoclonal antibody and the monoclonal anti-eosinophil cationic protein antibody. RESULTS We found that the number of eosinophils in the AS group was greater than that in the AR+ group (p < 0.05) and in the AR- group (p < 0.01). Moreover, the eosinophil count was lower in the AR- group compared with the AR+ group (p < 0.05). Similarly, the number of EG2+ cells was greater in the AS group than in the AR group (p < 0.02) and the AR- group (p < 0.05). Moreover, the EG2+ cell count was lower in the AR- group than in the AR+ group (p < 0.05). The number of mast cells and basophils in the AS group was greater than that in the AR group (p < 0.05 and p < 0.01, respectively). Mast cells in sputum were tryptase-positive. Basophils were present in sputum from 23% of patients with AR and 53% of patients with asthma. There was a significant correlation between methacholine PD20 and eosinophils (p < 0.005) and mast cells (p < 0.02) but not with basophils in those patients showing a measurable methacholine PD20 (AR+ and AS groups). CONCLUSIONS Inflammatory cells are present not only in the airways of patients with asthma but also in airways of patients with seasonal AR, even outside natural exposure. Moreover, we provide evidence for the presence of basophils in sputum of patients with asthma even during clinical remission. The presence of bronchial responsiveness is associated with an increase in the number of eosinophils and metachromatic cells. Our findings are consistent with the hypothesis that eosinophils, as well as mast cells, contribute to bronchial responsiveness not only in AS but also in seasonal AR.

Effect of intranasal azelastine and beclomethasone dipropionate on nasal symptoms, nasal cytology, and bronchial responsiveness to methacholine in allergic rhinitis in response to grass pollens

BACKGROUND We compared the effect of nasal azelastine (0.56 mg/day), nasal beclomethasone dipropionate (BDP, 200 micrograms/day) and matched placebo on seasonal symptoms, nasal cytology, and the increase in bronchial responsiveness occurring during pollen season in a group of subjects with history of allergic rhinitis to grass pollens only. METHODS The study was completed by nine subjects in the azelastine group, 13 subjects in the BDP group, and 13 subjects in the placebo group. Treatments were randomly administered for 6 weeks. Each subject recorded daily nasal, eye and chest symptoms and additional treatment requirement for the entire pollen season. Each subject performed nasal lavage 4 weeks into the pollen season. Bronchial responsiveness to methacholine was measured before and 4 weeks into the pollen season. Response was expressed as provocative dose causing a 20% fall in forced expiratory volume in 1 second in micromoles. RESULTS Azelastine-treated subjects had significantly fewer nasal symptoms during week 4 (p < 0.05), and BDP-treated subjects had fewer nasal symptoms during week 4 (p < 0.05) and week 5 (p < 0.05) compared with subjects given placebo. Both treatments significantly reduced the need for additional medications. BDP, but not azelastine, treatment significantly reduced the percent of eosinophils recovered in nasal lavage (p < 0.05). Neither azelastine nor BDP protected against the increase in bronchial responsiveness to methacholine occurring during the pollen season. CONCLUSION We demonstrated that both azelastine and BDP are effective treatments for nasal symptoms of seasonal allergic rhinitis after 4 weeks of therapy. However, we were not able to demonstrate an antiinflammatory activity of nasally administered azelastine. Nasal therapy with azelastine and BDP did not block the increase in bronchial responsiveness to methacholine caused by seasonal allergen exposure.

Bronchial responsiveness and airway inflammation in patients with nonallergic rhinitis with eosinophilia syndrome

BACKGROUND Nonallergic rhinitis with eosinophilia syndrome (NARES) is characterized by persistent nasal symptoms without allergy and by a marked eosinophil recruitment in the nasal cavities. OBJECTIVE We studied whether patients with NARES had bronchial responsiveness to methacholine and airway inflammation and examined the relationship between these factors. METHODS We selected a group of 39 patients referred to our allergy clinic for symptoms of perennial rhinitis. Atopic status was excluded by skin prick tests and RASTs. None of the patients had a history of respiratory symptoms. We preliminarily performed nasal lavage in all patients, and the diagnosis of NARES was made on the basis of the presence of at least 10% eosinophils in nasal lavage fluid. A methacholine challenge and sputum induction were also done on two different days. RESULTS Eosinophils in nasal lavage fluid ranged between 10% and 86%. Serum IgE levels were within normal range. Total circulating eosinophils ranged between 40 and 890/mm3. Methacholine PD20 values were measurable in only 18 patients (range, 0.32 to 22.56 micromol; group 1). In the remaining 21 patients, methacholine PD20 values were greater than 24 micromol (group 2). We found that differential cell counts in nasal lavage fluid in group 1 were not different from those in group 2. Methacholine PD20 values were not significantly related to any cell count in the nasal lavage fluid. Induced sputum was accomplished only in 22 patients. Eosinophils in induced sputum ranged between 0% and 56.5%. Numbers of total cells, macrophages, lymphocytes, neutrophils, and epithelial cells in the two subgroups were not different. The number of metachromatic cells tended to be higher in group 1 compared with group 2 (0.31% vs 0.05%), but the difference was not significant. The eosinophil count in the induced sputum was significantly higher in group 1 compared with group 2 (16.8% vs 3.1%; p < 0.05). In the entire population, methacholine PD20 values were significantly correlated with the number of eosinophils in sputum (r = -0.63; p < 0.001). CONCLUSION We showed that 46% of patients with NARES but without histories of respiratory symptoms had a measurable bronchial responsiveness. The presence of bronchial responsiveness was associated with an increased number of eosinophils in induced sputum but not with the inflammatory process in the nose.

Late bronchial response and increase in methacholine hyperresponsiveness after exercise and distilled water challenge in atopic subjects with asthma with dual asthmatic response to allergen inhalation

We investigated the occurrence of late asthmatic response and increased methacholine responsiveness after exercise and ultrasonically nebulized distilled water (UNDW) inhalation in 12 subjects with asthma with dual asthmatic response and increased responsiveness after allergen challenge. On 3 separate days, allergen, exercise, and UNDW challenges were performed 2 hours after methacholine. FEV1 was measured for 8 hours to detect any delayed change in airway caliber. If there were a further significant reduction in FEV1 after the recovery from the immediate bronchoconstriction, methacholine challenge was performed again when FEV1 had returned to baseline. Reproducibility of any observed late response to exercise and UNDW was also investigated by repeating these challenges on 2 subsequent days. After allergen inhalation only nine subjects had an early asthmatic response, whereas all the tested subjects demonstrated a late reaction and increased methacholine responsiveness. Ten subjects had an immediate response to exercise, and this was followed by a late response in only four patients. Nine subjects demonstrated early response to UNDW inhalation, and five subjects also had a late reaction. These late responses were associated with an increase in methacholine responsiveness in a subset of the tested subjects. Late-phase reactions to exercise and UNDW were not reproducible.

Psychological Implications of Respiratory Health and Disease

The possibility that a subject’s psychological status may influence respiratory sensations and that chronic respiratory disease may have psychological consequences has sparked great interest among clinicians and researchers. This paper reviews the existing research on the association between respiratory symptom perception and the psychological status and between chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease, and psychological disturbances. Moreover, it focuses on the role of stressful events in determining asthma exacerbations. The recent literature suggests that in patients with chronic respiratory diseases, the evaluation of breathlessness perception, psychological disturbances and the recording of any stressful events should be considered as relevant as the physical and functional assessment of respiration.

Assessment of Breathlessness Perception by Borg Scale in Asthmatic Patients: Reproducibility and Applicability to Different Stimuli

In asthmatics, the score of bronchoconstriction-associated breathlessness at 20% fall in forced expiratory volume at first second (FEV1) evaluated on a Borg scale (PS20) is a tool successfully used to measure the perception of symptoms. This prospective laboratory study evaluated the applicability of PS20 to assess the breathlessness induced by ultrasonically nebulized distilled water (UNDW) and methacholine (M) and its reproducibility. Twenty-two mild and clinically stable asthmatic patients performed UNDW and M challenge tests. The PS20 was calculated by linear interpolation of the last two points of the perception/fall in FEV1 curve of the UNDW and M tests. The reproducibility of PS20 M was assessed by repeating measurements on 2 separate days by 3 weeks. PS20 UNDW and PS20 M did not differ and were respectively 1.82 ± 1.85 and 2.03 ± 1.86. They were significantly related (rs = 0.63; p<0.01) and the bias between PS20 UNDW and PS20 M was –0.21 with the limits of agreement ranging from –3.2 to 3.6. The intraclass correlation coefficient for repeated measurement of PS20 M was 0.82; the bias between the two measurements was 0.2 with the limits of agreement ranging from –2.8 to 3.2. All patients had a measurable breathlessness perception degree on a Borg scale during both distilled water challenges and methacholine. Asthmatic patients with normal, exaggerated or poor breathlessness perception were also similar for both stimuli. In addition, PS20 showed a good reproducibility and this allows the serial evaluation of patients breathlessness perception by this technique in clinical settings and in the physiology laboratory.

Efficacy and Safety of Moguisteine in Comparison with Dextromethorphan in Patients with Persistent Cough

SummaryCough is a protective mechanism and an important symptom of many respiratory diseases. When coughing is only an annoying reflex and produces no mucus clearance, inducing fatigue or exhaustion for patients and worsening their pathological condition, antitussive drugs may be indicated.In this study we evaluated the efficacy and safety of moguisteine, a new antitussive drug with a peripheral mechanism of action, in a population of 124 adult patients with persistent cough associated with various respiratory disorders. Obstructive chronic bronchitis, reported in about 50% of the study population, was the most frequent underlying diagnosis. We conducted a randomised single-blind short term treatment trial in 7 centres, comparing moguisteine (3 doses of 200mg, over 2 days) to dextromethorphan (3 doses of 30mg, over 2 days). The primary efficacy variable was the percentage reduction in the audio tape-recorded number of coughs during a 6-hour period in the morning after the last dose of the study drug versus a 6-hour recording at baseline.Patients’ subjectively assessed visual analogue scale (VAS) scores of cough frequency and cough troublesomeness at night and during the morning were considered as secondary efficacy variables.Safety was assessed by means of routine clinical laboratory tests and adverse event monitoring.The postdrug percentage reduction in the number of coughs approached 30% on either drug. VAS scores of cough frequency and cough troublesomeness showed remarkable reductions in both groups, without any noteworthy difference between treatments. Possible or probable drug-related adverse events were reported in 3 of 61 patients on moguisteine (1 heartburn, 1 gastric pain, 1 diarrhoea) and in 4 of 63 patients on dextromethorphan (1 rhinitis and slight decrease of white blood cell count, 1 syncope, 1 gastric discomfort, 1 diarrhoea). Treatment discontinuation was necessary only for 1 patient, who had a syncope after the first dose of dextromethorphan.Our results indicate that treatment with moguisteine rapidly induces substantial cough relief and that it is well tolerated and as effective as dextromethorphan.

Effect of Inhaled Furosemide and Cromolyn on Bronchoconstriction Induced by Ultrasonically Nebulized Distilled Water in Asthmatic Subjects

BACKGROUND Inhaled furosemide has been shown recently to produce a protective effect against bronchoconstriction induced by several indirect stimuli, including ultrasonically nebulized distilled water (UNDW). Since there is a close parallel between its experimental effects and those reported for cromolyn,/it has been suggested that they may share some common mechanisms of action. Their protective effect, however, has never been compared directly. In this study, therefore, we have investigated the ability of equal doses (30 mg) of inhaled furosemide and cromolyn to modulate bronchoconstriction induced by UNDW in a group of ten asthmatic patients. METHODS Subjects with documented bronchial response to UNDW were enrolled in a randomized, double-blind, placebo-controlled study. Treatments were administered five minutes prior to increasing outputs of UNDW and the response was expressed as the provocative output causing a 20% fall in FEV1 (PO20, in mL/min) and as the output-response slope. RESULTS Geometric mean PO20 increased from 1.53 to 4.05 mL/min (P < .0004) after furosemide. After inhaling the highest output of UNDW (5.2 mL/min), PO20 was not measurable in six of ten patients when pretreated with furosemide and in all patients when pretreated with cromolyn. This difference was statistically significant (P < .05). Geometric mean values of output-response slope significantly decreased from 13.6 to 2.97 after furosemide (P < .0001) and from 13.6 to 1.43 (P < .0002) after cromolyn. CONCLUSIONS These results suggest that cromolyn has a slightly greater anti-reactive activity in UNDW-induced bronchoconstriction compared to furosemide.

Effect of acetazolamide on cough induced by low-chloride-ion solutions in normal subjects: Comparison with furosemide ☆ ☆☆ ★

BACKGROUND The antitussive activity of inhaled furosemide has been attributed to its blocking effect on the Na(+)-2Cl(-)-K+ cotransporter. It is likely that the antitussive activity of inhaled diuretics is more complex because amiloride, a diuretic that has no effect on the Na(+)-2Cl(-)-K+ cotransporter, also shows a significant effect against cough induced by low-chloride-ion solutions. Apart from pharmacokinetics of inhaled diuretics, this activity could also depend on the inhibition of carbonic anhydrase. OBJECTIVES We therefore studied the effect of inhaled acetazolamide, a selective inhibitor of carbonic anhydrase activity, on cough induced by the inhalation of different chloride ion solutions in a group of normal subjects. This was compared with the antitussive effect of furosemide. In addition, we attempted to determine whether the effect of acetazolamide is dose-dependent. METHODS Cough challenge consisted of consecutive inhalations of four solutions having decreasing concentrations of chloride ions (150, 75, 37.5 and 0 mmol/L). Nine normal subjects underwent the cough challenge 5 minutes after the inhalation of saline placebo, acetazolamide (500 mg), and furosemide (30 mg) according to a randomized, double-blind study design. A group of six subjects were challenged according to the same procedure and study design, after the inhalation of saline placebo and of two doses of acetazolamide (250 mg and 500 mg). RESULTS Inhaled acetazolamide significantly reduced cough response to 37.5 and 0 mmol/L chloride solutions compared with placebo (p less than 0.015 and p less than 0.015, respectively). Furosemide showed a similar protective effect (p less than 0.015 and p less than 0.025, respectively). Acetazolamide provided a significantly better protective effect than furosemide (p less than 0.025 and p less than 0.015, respectively). The antitussive activity of the two doses of acetazolamide was not statistically different. CONCLUSION These results demonstrate that inhaled acetazolamide, a selective inhibitor of carbonic anhydrase, attenuates cough induced by low-chloride-ion solutions in normal subjects. At the applied doses, its antitussive activity is slightly greater than furosemide. This finding suggests that the inhibition of carbonic anhydrase activity is likely involved in modulating changes caused by absence of a chloride ion in the airway microenvironment of human beings.