Strategy aimed at reduction of sputum eosinophils decreases exacerbation rate in patients with asthma. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils, and exhaled nitric oxide levels in patients with asthma. Effects of different anti-asthmatic agents on induced sputum and eosinophil cationic protein in mild asthmatics. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Effects of aerobic training on airway inflammation in asthmatic patients. The effect of montelukast on eosinophil apoptosis: induced sputum findings of patients with mild persistent asthma. Treatment of asthma patients with herbal medicine TJ-96: a randomized controlled trial. Salmeterol plus fluticasone propionate versus fluticasone propionate plus montelukast: a randomised controlled trial investigating the effects on airway inflammation in asthma.
Under Global Initiative for Asthma guidelines, the clinical control of disease activity and the adjustment of treatment in patients with asthma are based on symptoms, use of rescue medication, lung function and peak expiratory flow measurement (standard strategy). We investigated whether a strategy to reduce the number of sputum eosinophils (EOS strategy) gives better clinical control and a lower exacerbation rate compared with the standard strategy. Fifty-five patients with moderate to severe asthma entered this open, randomized, parallel-group study and visited the out-patient department every 3 months for 18 months. The dose of corticosteroids was adjusted according to the standard strategy or the percentage of sputum eosinophils (EOS strategy). During the study period, the EOS strategy led to a significantly lower incidence of asthma exacerbations compared with the standard strategy group (0.22 and 0.78 exacerbations per year per patient, respectively). There were significant differences between the strategies in time to first exacerbation. Treatment decisions in asthma are based on assessments of symptoms and simple measures of lung function, which do not relate closely to underlying eosinophilic airway inflammation. We aimed to assess whether a management strategy that minimises eosinophilic inflammation reduces asthma exacerbations compared with a standard management strategy.
                We recruited 74 patients with moderate to severe asthma from hospital clinics and randomly allocated them to management either by standard British Thoracic Society asthma guidelines (BTS management group) or by normalisation of the induced sputum eosinophil count and reduction of symptoms (sputum management group). We assessed patients nine times over 12 months. The results were used to manage those in the sputum management group, but were not disclosed in the BTS group. The primary outcomes were the number of severe exacerbations and control of eosinophilic inflammation, measured by induced sputum eosinophil count. Analyses were by intention to treat.
                The sputum eosinophil count was 63% (95% CI 24-100) lower over 12 months in the sputum management group than in the BTS management group (p=0.002). Patients in the sputum management group had significantly fewer severe asthma exacerbations than did patients in the BTS management group (35 vs 109; p=0.01) and significantly fewer patients were admitted to hospital with asthma (one vs six, p=0.047). The average daily dose of inhaled or oral corticosteroids did not differ between the two groups.
                A treatment strategy directed at normalisation of the induced sputum eosinophil count reduces asthma exacerbations and admissions without the need for additional anti-inflammatory treatment. Airway hyperresponsiveness, induced sputum eosinophils, and exhaled nitric oxide (NO) levels have all been proposed as non-invasive markers for monitoring airway inflammation in patients with asthma. The aim of this study was to compare the changes in each of these markers following treatment with inhaled glucocorticosteroids in a single study.
                In a randomised, double blind, placebo controlled, parallel study 25 patients with mild asthma (19-34 years, forced expiratory volume in one second (FEV1) >75% predicted, concentration of histamine provoking a fall in FEV1 of 20% or more (PC20) <4 mg/ml) inhaled fluticasone propionate (500 microg twice daily) for four weeks. PC20 to histamine, sputum eosinophil numbers, and exhaled NO levels were determined at weeks 0, 2, and 4, and two weeks after completing treatment. Sputum was induced by inhalation of hypertonic (4.5%) saline and eosinophil counts were expressed as percentage non-squamous cells. Exhaled NO levels (ppb) were measured by chemiluminescence.
                In the steroid treated group there was a significant increase in PC20, decrease in sputum eosinophils, and decrease in exhaled NO levels compared with baseline at weeks 2 and 4 of treatment. Subsequently, each of these variables showed significant worsening during the two week washout period compared with week 4. These changes were significantly different from those in the placebo group, except for the changes in sputum eosinophils and exhaled NO levels during the washout period. There were no significant correlations between the changes in the three markers in either group at any time.
                Treatment of asthmatic subjects with inhaled steroids for four weeks leads to improvements in airway hyperresponsiveness to histamine, eosinophil counts in induced sputum, and exhaled nitric oxide levels. The results suggest that these markers may provide different information when monitoring anti-inflammatory treatment in asthma. Inhaled corticosteroids, leukotriene receptor antagonists, and theophylline are recommended for the treatment of mild persistent asthma. The aim of this study was to compare the changes in sputum total cell and eosinophil counts, and eosinophil cationic protein (ECP) levels in serum and sputum following treatment with leukotriene receptor antagonists, inhaled corticosteroids, and theophylline in patients with mild persistent asthma.
                Total cell counts, eosinophil percentage, and ECP levels in induced sputum and serum were determined both before and after treatment. Prior to sputum induction, FEV1 and PEF values and symptom scores were recorded at baseline and after 8 weeks of treatment. After baseline measurements, the asthmatic patients (n = 30) were randomized into three groups. A total of 10 patients were treated with zafirlukast, 20 mg bd, 10 with budesonide inhaler 200 microg bd, and 10 with theophylline 200 mg bd.
                There were significant decreases in sputum total cell counts and eosinophil percentage in all treatment groups. However, the decrease in sputum eosinophil counts was more significant in the corticosteroid-treated group. Although sputum ECP levels decreased significantly in the groups treated with zafirlukast and budesonide (zafirlukast group, 580-135 microg/L, P < 0.01; budesonide group, 683-268 microg/L, P < 0.01), the decrease was not statistically significant in the theophylline-treated group (498-361 microg/L, P > 0.05). In contrast, there were no significant changes in serum ECP levels in any of the treatment groups.
                All three treatments resulted in significant decreases in sputum total cell counts and eosinophil percentage, but the decrease in sputum ECP level was only seen in the groups treated with budesonide and zafirlukast. These results suggest that although all three treatments are considered as first-line treatments in most consensuses, theophylline seems to have less of an inhibitory effect on eosinophil activation. One important goal of asthma treatment is to reduce exacerbations. The current authors investigated if the use of sputum cell counts to guide treatment would achieve this goal. A total of 117 adults with asthma were entered into a multicentre, randomised, parallel group-effectiveness study for two treatment strategies over a 2-yr period. In one strategy (the clinical strategy: CS) treatment was based on symptoms and spirometry. In the other (the sputum strategy: SS) sputum cell counts were used to guide corticosteroid therapy to keep eosinophils<or=2%; symptoms and spirometry were used to identify clinical control, exacerbations and other treatments. Patients were blind to sputum cell counts in both strategies and physicians were blind in the CS, thus removing bias. First, the minimum treatment to maintain control was identified in 107 patients (Phase 1) and then this treatment was continued (Phase 2) for the remaining of the 2 yrs. The primary outcomes were the relative risk reduction for the occurrence of the first exacerbation in Phase 2 and the length of time without exacerbation. The current authors also examined the type and severity of exacerbations and the cumulative dose of inhaled steroid needed. The duration and number of exacerbations in Phase 1 were similar in both groups. In Phase 2 there were a 126 exacerbations of which 79 occurred in the CS (62.7%) and 47 (37.3%) in the SS groups. The majority of the 126 exacerbations (101; 80.1%) were mild. The majority of the 102 exacerbations, where sputum examination was performed before any treatment (n=70), were noneosinophilic. In the SS patients, the time to the first exacerbation was longer (by 213 days) especially in those considered to need treatment with a long acting beta2-agonist (by 490 days), the relative risk ratio was lower (by 49%), and the number of exacerbations needing prednisone was reduced (5 versus 15). This benefit was seen mainly in patients needing treatment with inhaled steroid in a daily dose equivalent to fluticasone>250 microg, and was due to fewer eosinophilic exacerbations. The cumulative dose of corticosteroid during the trial was similar in both groups. Monitoring sputum cell counts was found to benefit patients with moderate-to-severe asthma by reducing the number of eosinophilic exacerbations and by reducing the severity of both eosinophilic and noneosinophilic exacerbations without increasing the total corticosteroid dose. It had no influence on the frequency of noneosinophilic exacerbations, which were the most common exacerbations. there is evidence suggesting that physical activity has anti-inflammatory effects in many chronic diseases; however, the role of exercise in airway inflammation in asthma is poorly understood. We aimed to evaluate the effects of an aerobic training program on eosinophil inflammation (primary aim) and nitric oxide (secondary aim) in patients with moderate or severe persistent asthma.
                sixty-eight patients randomly assigned to either control (CG) or aerobic training (TG) groups were studied during the period between medical consultations. Patients in the CG (educational program + breathing exercises; N = 34) and TG (educational program + breathing exercises + aerobic training; N = 34) were examined twice a week during a 3-month period. Before and after the intervention, patients underwent induced sputum, fractional exhaled nitric oxide (FeNO), pulmonary function, and cardiopulmonary exercise testing. Asthma symptom-free days were quantified monthly, and asthma exacerbation was monitored during 3 months of intervention.
                at 3 months, decreases in the total and eosinophil cell counts in induced sputum (P = 0.004) and in the levels of FeNO (P = 0.009) were observed after intervention only in the TG. The number of asthma symptom-free days and VO(2max) also significantly improved (P < 0.001), and lower asthma exacerbation occurred in the TG (P < 0.01). In addition, the TG presented a strong positive relationship between baseline FeNO and eosinophil counts as well as their improvement after training (r = 0.77 and r = 0.9, respectively).
                aerobic training reduces sputum eosinophil and FeNO in patients with moderate or severe asthma, and these benefits were more significant in subjects with higher levels of inflammation. These results suggest that aerobic training might be useful as an adjuvant therapy in asthmatic patients under optimized medical treatment. Apoptosis may be important in limiting airway eosinophilia. Treatment with leukotriene antagonists decreases the number of eosinophils in both peripheral blood and sputum.
                To assess the effect of montelukast on eosinophil apoptosis in a group of patients with mild persistent asthma (MPA) and to compare this effect with the apoptotic effect of fluticasone propionate (FP).
                Randomly selected patients with MPA (n = 22) who had not taken anti-inflammatory therapy within the preceding 12 months were included in the study. The sputum induction procedure was performed and the patients were divided into two groups: group 1 (n = 10) received FP 250 microg/day and group 2 (n = 22) received montelukast 10 mg/day orally for 4 weeks. Sputum induction was repeated after the treatment period. The resulting cytospin slides were stained by Wright's stain and morphologic changes in apoptotic eosinophils were assessed by the use of light microscopy by two blinded expert pathologists. Serum soluble Fas ligand (sFasL) concentrations were measured by an ELISA method at baseline and after treatment in both groups, as well as in a group of healthy subjects.
                In within-group comparisons, the apoptotic ratio (AR) increased at the end of the study period in group 1 (p = 0.05). In the group treated with FP the ratio of sputum eosinophils significantly decreased (p = 0.02), and the AR significantly increased (p < 0.005). No differences were found in the two study groups in serum sFasL levels at the end of the treatment period compared with baseline values (p > 0.05).
                Our findings demonstrate that 4 weeks' treatment with a CysLT receptor antagonist (montelukast) resulted in an increase in eosinophil apoptosis comparable to that produced by FP, suggesting that induction of apoptosis may be a potential mechanism for the mode of action of CysLT receptor antagonists in asthma. Alternative medicine use has increased at a remarkable pace all over the world in recent years. Although herbal medicine for the treatment of asthma is becoming the focus of public attention, randomized studies had not been performed, even in Eastern countries including Japan. This study was designed to investigate whether one of the Japanese government approved herbal complexes Saiboku-to (TJ-96) is effective for the treatment of atopic asthma, and to investigate whether this protective activity is associated with a reduction in eosinophilic inflammation. A double-blind, randomized, crossover design was used. Subjects received 2.5 g of TJ-96 or placebo orally 3 times daily for 4 weeks and then, after a washout period of at least 4 weeks, crossed over to receive the alternative treatment. We assessed the effects of pretreatment with TJ-96 on bronchoconstriction precipitated by inhalation of methacholine. Furthermore, eosinophil counts and measurement of eosinophilic cationic protein (ECP) were performed. After 4 weeks of treatment with TJ-96, values of PC20 -methacholine significantly improved in the treatment with TJ-96. Also, patients' symptoms, blood eosinophils, serum ECP, sputum eosinophils, and sputum ECP were significantly decreased. Our results suggest that TJ-96 has an antiinflammatory effect on bronchial eosinophilic infiltration. This study raises further interesting therapeutic possibilities and argues for further trials of new approaches to the treatment of asthma. Few studies have compared treatment strategies in patients with asthma poorly controlled on low dose inhaled corticosteroids, and little is known about the effects of different treatments on airway inflammation. In this double-blind, placebo-controlled, parallel group study, we compared the effects of salmeterol plus fluticasone propionate (FP) (Seretide; SFC) and FP plus montelukast (FP/M) on sputum inflammatory markers, airway responsiveness, lung function, and symptoms in adult asthmatics.
                Sixty-six subjects were randomised to SFC or FP/M for 12 weeks. The primary outcome was changes in neutrophil, eosinophil, macrophage, lymphocyte, and epithelial cell levels in induced sputum. Additional outcomes included the change in other sputum markers of airway inflammation, airway responsiveness, symptom control, and lung function.
                Both treatments had no significant effect on induced sputum inflammatory cells, although there was a trend for a reduction in sputum eosinophils. Both treatments significantly improved airway responsiveness, whereas SFC generally led to greater improvements in symptom control and lung function than FP/M. FP/M led to significantly greater reductions in sputum cysteinyl leukotrienes than SFC (treatment ratio 1.80; 95% CI 1.09, 2.94).
                Both treatments led to similar control of eosinophilic airway inflammation, although PEF and symptom control were better with SFC. STUDY NUMBER: SAM40030 (SOLTA).
Tailored asthma interventions based on sputum eosinophils is beneficial in reducing the frequency of asthma exacerbations in adults with asthma. This review supports the use of sputum eosinophils to tailor asthma therapy for adults with frequent exacerbations and severe asthma. Further studies need to be undertaken to strengthen these results and no conclusion can be drawn for children with asthma.