Methylprednisolone pulse therapy in severe acute asthma

In a group comparative double blind pilot study six asthmatic patients with an acute exacerbation of their disease were randomly treated with either methylprednisolone pulse therapy (MPPT) (1000 mg daily for 3 days) (n = 2) followed by placebo tablets, or standard doses of methylprednisolone (MP) (50 mg daily gradually decreased to zero over 3 weeks) (n = 4). The results showed that the effect of MPPT did not differ from that of standard doses of MP. MPPT has, however, the potential of being preferable to standard treatment with MP, because of easy administration and optimal patient compliance.     

Bronchial inflammation in corticosteroid-sensitive and corticosteroid-resistant asthma at baseline and on oral corticosteroid treatment

BACKGROUND: Pathophysiology of corticosteroid (CS)-resistant asthma remains incompletely understood. OBJECTIVE: To determine if failure of asthma to clinically improve with CS is due to a defective response of airway bronchial inflammation to these drugs. METHODS: Twenty-one asthmatics having a decreased baseline FEV1 that improved >or= 30% with inhaled beta2 agonist got bronchial biopsies before and at the end of an oral CS treatment (methylprednisolone 40 mg daily for 14 days). They were arbitrarily divided into two groups according to baseline FEV1 improvement following this treatment: >or= 23% designated as CS-sensitive (CSS) (n = 10) and < 15% as CS-resistant (CSR) (n = 11). RESULTS: Before oral CS, counts of bronchial mucosa inflammatory cells identified by immunohistochemistry (CD3, MBP, tryptase, CD68, neutrophil elastase and CD25 for lymphocytes, eosinophils, mast cells, macrophages, neutrophils and IL-2 receptors, respectively) were similar in CSS and CSR subjects. Oral CS decreased CD3+ cell counts (medians: 60-20 cells/mm(2); P = 0.014) and MBP+ cell counts (medians: 19-4 cells/mm(2); P = 0.03) in CSS asthmatics, but only tryptase+ cell counts in CSR asthmatics (medians: 30-18 cells/mm(2); P = 0.05). Few bronchial neutrophil elastase+ cells were observed and their counts were similar in the two groups of asthmatics before and when on oral CS (all medians: = 2 cells/mm(2)). CONCLUSIONS: These data show that, in these subjects with moderate to severe asthma, lymphocytes and eosinophils constitute most of the inflammatory cells infiltrating the bronchial mucosa. They also demonstrated that clinical impaired response to CS is associated with a persistent bronchial mucosa cellular infiltrate despite oral CS treatment. Additional studies are required to determine the role of this CS-resistant bronchial inflammation in the impaired asthma clinical response to these drugs.     

Obtaining concomitant control of allergic rhinitis and asthma with a nasally inhaled corticosteroid

Allergic rhinitis (AR) and asthma coexist frequently and a dual treatment is recommended by prescribing topical nasal plus oral inhaled corticosteroids. The purpose of this study was to assess the efficacy of a nasally inhaled corticosteroid aiming at concomitant control of AR and asthma. A controlled trial was conducted among 60 patients with AR and asthma, aged 6-18 years, who were randomized into two groups. During 8 weeks, the experimental group (30 patients) received exclusively fluticasone propionate hydrofluoroalkane (FP-HFA) inhaled through the nose (mouth closed) using a large volume spacer attached to a face mask. The comparison group (30 patients) received a nasal spray of isotonic saline plus oral inhalation of FP-HFA through a mouthpiece attached to the same spacer. Clinical scores for AR and asthma, nasal inspiratory peak flow (NIPF), and spirometry were assessed by blinded observers. There was a significant improvement in AR scores and NIPF in the experimental group (P or= 0.20). Prebronchodilator FEV(1) (% predicted value) improved by 10% in both groups, comparing values at inclusion with those obtained at the end of follow up. Our results suggest that nasally inhaled FP-HFA through a spacer may control AR and asthma in children and adolescents. This approach is likely to result in higher compliance, lower costs, and fewer side effects.     

Adherence rate to inhaled corticosteroids and their impact on asthma control

Background:  Poor asthma control is associated to high morbidity. The objective of this study was to assess the association between adherence rates to beclomethasone dipropionate (BDP) and the degree of asthma control.
Methods:  A cohort concurrent study was carried out for 12 months with 122 asthmatic patients, aged 3–12 years, randomly selected in a pediatric pulmonology outpatient clinic, who received BDP free of charge. Adherence rates were verified by pharmacy records. Clinical control was assessed through a scoring system comprised four variables (nocturnal and morning symptoms, limitation of physical activities and exacerbations). Total score was 16 points. Patients whose score was below or equal to two were considered controlled (group 1), and patients whose score was above or equal to three were considered uncontrolled (group 2). For patients able to perform spirometry, we considered as controlled the patients with forced expiratory volume in 1 s (FEV₁) equal to or above 80% of the predicted value, and as uncontrolled the patients with FEV₁ below 80%.
Results:  Fewer than half (40.3% maximum) of the 122 patients maintained asthma control. Median adherence rate of groups 1 and 2 were 85.5% and 33.8%, ( P  < 0.001) in the 4th month, 90.0% and 48.0% ( P  < 0.001) in the 8th month and 84.4% and 47.0% in the 12th month ( P  < 0.001), respectively.
Conclusion:  In all periods, there were statistically significant differences in adherence rates for maintaining or not maintaining the asthma control. Optimal asthma control entailed adherence rate higher than 80%. Strategies for reducing asthma morbidity should include a regular monitoring of adherence to inhaled steroids.     

Evaluation of serum eosinophil cationic protein as a predictive marker for asthma exacerbation in patients with persistent disease

BACKGROUND: Eosinophilic inflammation is a feature of asthma. However, serological markers to indicate eosinophil activation in this process are not fully defined. OBJECTIVE: To evaluate the relationship of serum eosinophil cationic protein (ECP) to asthma worsening and a marker for treatment effectiveness, 26 adult patients with an asthma exacerbation were identified. METHODS: Identified asthma subjects were treated with oral corticosteroids (prednisone) for 14 days. The lung function variables, forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF), were determined as percentage of predicted and the blood total eosinophil count and serum ECP levels were measured. Patients were re-evaluated after 14 days of corticosteroid treatment and then every 3 months thereafter during a 12-month period. RESULTS: Eighteen patients responded to prednisone treatment, whereas eight did not, assessed as improvement of their lung function parameters. Different serum ECP patterns could be seen in the responders compared with the non-responders. All 18 responders had considerably increased serum ECP at the time of exacerbation, whereas the non-responders had lower serum ECP levels. The serum ECP levels decreased to a greater extent in the responder patient group than in the non-responder patients following prednisone treatment. This difference in patterns was not seen with total blood eosinophil counts. CONCLUSION: Our findings suggest that serum ECP may be used to predict a response to corticosteroid therapy in adult patients with asthma.     

Methotrexate therapy of oral corticosteroid-dependent asthmatics reduces serum immunoglobulins: correlation with clinical response to therapy

BACKGROUND: Concomitant methotrexate (MTX) therapy of oral corticosteroid (CS)-dependent asthmatics has been shown to spare CS therapy, but the mechanism is unknown. In a previous report, we showed that MTX increases T cell inhibition by CS. In this report we focus on effects of MTX on immunoglobulin concentrations and their possible clinical relevance. OBJECTIVE: To monitor changes in circulating leucocytes and Ig in a group of these patients during MTX therapy, and to relate these changes to clinical 'response' as defined by oral CS reduction. METHODS: Sixteen severe asthmatics dependent on oral prednisolone 15 (7.5-25) mg/day in addition to high dose inhaled CS were treated with MTX 15 mg intramuscularly, weekly for 28 weeks. Prednisolone dosages were maintained constant for 12 weeks then reduced systematically over the next 16 weeks provided that asthma control did not deteriorate. Patients were classified a priori as 'responders' or 'non-responders' to MTX (reduction of initial oral prednisolone requirement by >or=50% or <50%, respectively). Patients were followed-up for a further 12 weeks after MTX withdrawal. Serum Ig and differential blood leucocyte counts were measured at baseline, 12, 28 and 40 weeks. RESULTS: MTX therapy allowed significant, but individually variable, reductions in oral prednisolone dosages (P<0.00001) without alteration of lung function or symptoms. This was associated with significant reductions in mean serum concentrations of Ig of all classes, which reversed following MTX withdrawal. Reductions in IgE and IgG were significantly greater in the MTX 'responders' as compared with 'non-responders', and changes in IgE, IgG and IgM correlated with changes in prednisolone requirements. Differential blood leucocyte counts showed no significant variation. CONCLUSION: MTX therapy reduced oral CS requirements in these severe asthmatics to a degree which correlated with reduced circulating Ig but not lymphopaenia, suggesting a possible cause and effect relationship. These reductions might also contribute to the documented incidence of opportunistic infection in these circumstances.     

Direct and indirect bronchoprovocation tests in dose-response studies of inhaled corticosteroids: Past,present, and future directions

Inhaled corticosteroids (ICS) are a mainstay of treatment in eosinophilic asthma. Many studies have explored the dose-response effect of different formulations of ICS through direct or indirect bronchoprovocation testing. Such studies are important for investigating efficacy and identifying the relative potency between formulations. However, lack of consistency in methods and designs has hindered the comparability of study findings. This review discusses current knowledge of the dose-response, or lack thereof, of different formulations of ICS through direct and indirect bronchoprovocation testing. The strengths and weaknesses of past studies inform recommendations for future methodological considerations in this field, such as utilizing a randomized double-blind crossover design, enrolling participants likely to respond to ICS therapy, and carefully selecting treatment durations and washout periods to assess incremental improvement in airway hyperresponsiveness while reducing the likelihood of a carryover effect.     

Nasal inhalation of budesonide from a spacer in children with perennial rhinitis and asthma

The standard treatment of allergic rhinitis and asthma consists of topical corticosteroids administered intranasally and inhaled through the mouth. Although this therapy is highly effective, and side-effects are few and mild, it may be possible further to improve the therapeutic index and patient compliance with the treatment. In the present study, we evaluated a nasal inhalation system used for the simultaneous treatment of rhinitis and asthma. In principle, it results in an airway deposition of the corticosteroid similar to that of inhaled allergens. Twenty-four children with perennial rhinitis and asthma inhaled budesonide through the nose from a pressurized aerosol, attached to a spacer device, in a double-blind, placebo-controlled, crossover study. Compared with placebo, budesonide treatment resulted in a significant reduction of nasal symptoms (P<0.01) and of asthma symptoms (P<0.05), and in an increase of nasal peak inspiratory flow (P<0.001) and of oral peak expiratory flow (P=0.01). There were no differences between budesonide and placebo in local side-effects, such as dry nose, nosebleed, and hoarseness. We conclude that nasal inhalation of a corticosteroid from a spacer offers a simple and effective treatment for both rhinitis and asthma in children, but it is an open question whether the nasal inhalation system can improve the ratio of antirhinitis/antiasthma effects to side-effects.     

The effectiveness of intranasal corticosteroids in combined allergic rhinitis and asthma syndrome

Background Allergic rhinitis (AR) and asthma often coexist and may represent two manifestations of the same disease recently named combined AR and asthma syndrome (CARAS). Aim To review the common pathophysiology of combined AR and asthma and to investigate the efficacy of intranasal corticosteroids (INCS). Methods Medline was used to identify articles relevant to mechanisms. A Cochrane systematic review was performed to assess the efficacy of INCS in CARAS. Results There is cross‐talk, evidence of a common inflammatory response in both sites, linked by a systemic component. The efficacy of anti‐inflammatory INCS on asthma outcomes was assessed in a systematic review of 12 randomized controlled trials involving 425 subjects. After INCS there were non‐significant trends for improvement in asthma symptom score (standardized mean difference (SMD) of 0.61; P=0.07), forced expiratory volume in 1 s (SMD of 0.31; P=0.08), and morning peak expiratory flow (weighted mean difference of 36.51; P=0.06). There was no impact on methacholine airways responsiveness (SMD of ?0.20; P=0.4). The review identified two promising new treatment options in united airway disease such as INCS as monotherapy in rhinitis and mild asthma, and a combined intranasal and intrabronchial corticosteroid (IBCS) deposition technique. Conclusion Common mucosal inflammatory responses occur in CARAS. This systematic review shows trends for a benefit of INCS in CARAS, but recognizes that more research is needed. At this stage, the current best practice is to treat asthma conventionally with IBCS with or without β₂‐agonist and to add INCS to improve specific rhinitis symptoms.     

Lipid and protein metabolism in asthma. Effects of diet and corticosteroid therapy

BACKGROUND: Because little is known about the effects of asthma and asthma therapy on lipid and protein metabolism, we have investigated the characteristics of diet and plasma/serum levels of fat and protein in a group of asthma patients with various degrees of severity. METHODS: A case-control study was carried out on 118 asthma patients recruited from an outpatient clinic and 121 healthy subjects. Asthma severity was characterized in four groups according to clinical symptoms, lung-function tests, and therapy. Normal dietary intake was estimated from a food frequency questionnaire. Serum protein, albumin, and fatty acids were determined by standard methods. RESULTS: The dietary energy intake of the asthmatics was significantly lower than that of the controls. However, no differences in the body mass index were found between asthma patients and healthy subjects. There were no differences in serum/plasma levels in any of the measured biochemical parameters between healthy subjects and asthmatics. Plasma levels of protein and albumin were significantly lower in severely corticosteroid-dependent patients. There was a significant negative correlation between plasma protein (r=0.36, P<0.05) and plasma albumin levels (r=0.43, P<0.01) and the daily dose of oral corticosteroids. We did not find any differences in plasma levels of cholesterol, HDL-cholesterol, LDL-cholesterol, and fatty acids between cortico-dependent patients and those not receiving this therapy. No correlation was found between any biochemical parameters and the daily dose of inhaled corticosteroids. CONCLUSIONS: Our results suggest that asthma induces a decrease in energy intake that does not result in a decreased body weight. Inhaled corticosteroids do not exert any metabolic effect, whereas severe asthma with regular oral corticosteroid therapy is associated with reduced plasma protein and albumin levels.     

Effect of inhaled indomethacin in asthmatic patients taking high doses of inhaled corticosteroids

Background: Cyclooxygenase products of arachidonic acid may play a part in bronchoconstriction and airway inflammation in asthma. Objective: We sought to determine the effect of inhaled indomethacin on asthma control and asthma exacerbations during reduction of inhaled corticosteroids in patients with moderate-to-severe steroid-dependent asthma. Methods: We conducted a double-blind, randomized, parallel-group, multicenter study in 38 patients with asthma taking high doses (≥1500 μg/d) of beclomethasone dipropionate (BDP). After a run-in period, patients were assigned inhaled indomethacin (50 mg/d) or placebo for 6 weeks, during which the daily doses of BDP were reduced to half at week 2 and then to one third of the baseline dose at week 4. Results: Data were available from 34 patients. After the reduction of BDP doses, FEV₁, peak expiratory flow, asthma symptoms, and exhaled nitric oxide concentrations deteriorated in both treatment groups, but these effects were less pronounced in the indomethacin group compared with the placebo group. During the 6-week treatment period, 89% of the patients receiving placebo had relapse of asthma, whereas only 38% of those receiving inhaled indomethacin did so (P = .003). Conclusion: Inhalation of indomethacin can reduce asthma exacerbations induced by reduction of high-dose inhaled corticosteroid in steroid-dependent asthma. (J Allergy Clin Immunol 2000;105:1134-9.)     

口服白三烯受体拮抗剂与吸入糖皮质激素治疗小儿咳嗽变异型哮喘合并变应性鼻炎的对比研究

目的对比研究口服白三烯受体拮抗剂（LTRA）与吸入糖皮质激素（ICS）对dxJL咳嗽变异型哮喘合并变应性鼻炎的防治效果。方法54例2-5岁患儿随机分为LTRA组（27例）和ICS组（27例）。LTRA组口服孟鲁司特钠，每次4mg，睡前服用1次；ICS组患儿规律吸入布地奈德气雾剂，每日200-400μg，采用储雾罐辅助吸入。药物治疗3个月后继续随访观察15个月。结果LTRA组与ICS组比较．控制症状所需的平均天数为（8．31±3．69）d和（7．20±2．78）d；症状缓解率为92．6％和96．3％，差异无统计学意义（P〉0．05）。在病程的18个月LTRA组复发率（36．0％）显著高于ICM组（15．4％）。转化为典型哮喘者。LTRA组7例（28．0％），ICS组2例（7．7％），差异有统计学意义（P〈0．05）。结论口服LTRA控制小儿咳嗽变异型哮喘合并变应性鼻炎的近期疗效与ICS相当。可作为一线药物使用。但接受LTRA治疗的患儿远期复发率或者转化为典型哮喘的比率高于ICS治疗的患儿。     

Methotrexate therapy in asthma increases T cell susceptibility to corticosteroid inhibition

BACKGROUND: Concomitant methotrexate (MTX) therapy of severe, oral corticosteroid-dependent asthmatics has been shown to be corticosteroid sparing, but the mechanism is unknown. We hypothesized that MTX therapy of these patients increases the susceptibility of their T cells to corticosteroid inhibition. OBJECTIVE: To measure prednisolone inhibition of lectin-induced proliferation of peripheral blood T cells from a group of these patients before, during and following MTX therapy. METHODS: Eighteen severe asthmatics (median (range) age 56 (33-68) years, FEV1 61 (38-69)% predicted, dependent on oral prednisolone 15 (7.5-25) mg/day in addition to high-dose, inhaled corticosteroids) were treated with MTX 15 mg intramuscularly, weekly for 28 weeks. After 12 weeks of MTX, oral prednisolone dosages were reduced systematically over 16 weeks, provided that asthma control did not deteriorate. Patients were followed for a further 12 weeks after MTX withdrawal. Concentration-dependent, prednisolone inhibition of lectin-induced proliferation of peripheral blood T cells was measured just prior to MTX therapy (week 1) and at weeks 12, 28 and 40, and IC50 concentrations were interpolated. RESULTS: By week 28 of MTX therapy, patients were able to reduce oral prednisolone dosages from (median, SIQR) 15 (10-20.5) to 5.9 (1.4-9.4) mg/day (P<0.01) without alteration of lung function and symptoms, while median IC50 values for prednisolone inhibition of peripheral blood T cell proliferation were reduced from 49 (21-144) to 4 (1-9) nm (P<0.0001). These increased again to 15 (9.4-25.7) mg/day and 36 (18-67) nm, respectively, following MTX withdrawal. A correlation (P<0.01) was observed between percentage reductions in prednisolone dosages in vivo and fold changes in prednisolone IC50in vitro between weeks 12 and 28. CONCLUSION: This effect of MTX may at least partly account for its oral corticosteroid-sparing effect in severe asthma.     

Comparison of once- and twice-daily dosing of fluticasone propionate 200 micrograms per day administered by Diskus device in patients with asthma treated with or without inhaled corticosteroids

Background: There are limited published data regarding the efficacy of once- versus twice-daily administration of flutica-sone propionate. Objective: Our purpose was to evaluate the effectiveness of fluticasone propionate powder 200 μg/d administered as a once- or twice-daily dosage regimen in patients who were currently being treated with bronchodilators only (BD patients) and in patients who required inhaled corticosteroids for maintenance treatment of asthma (ICS patients). Methods: Five hundred seventy patients were randomly assigned to receive one of the following inhaled treatments through the Diskus device (Glaxo Wellcome, Research Triangle Park, NC) for 12 weeks: fluticasone propionate 100 μg twice daily (FP100BID) or 200 μg once daily (FP200QD) or placebo. Results: BD patients treated with FP100BID, FP200QD, and placebo had mean increases in FEV₁ from baseline to end point of 0.49 L, 0.37 L, and 0.21 L, respectively (P < .001, FP100BID vs placebo; P = .05, FP200QD vs placebo). ICS patients treated with FP100BID and FP200QD had mean increases in FEV₁ of 0.27 L and 0.11 L, respectively, compared with a decrease in FEV₁ of –0.08 L with placebo (P < .001, FP100BID vs placebo; P = .023, FP200QD vs placebo). BD patients treated with FP100BID and FP200QD had mean increases in morning peak expiratory flow from baseline to end point of 31 L/min and 27 L/min, respectively, compared with a 1 L/min increase in patients treated with placebo. ICS patients treated with FP100BID had a mean increase in morning peak expiratory flow (from baseline to end point) of 18 L/min compared with mean decreases of –3 L/min and –12 L/min in the FP200QD and placebo groups, respectively. More patients were withdrawn from placebo (26% and 48%, in BD and ICS patients, respectively) than from fluticasone propionate (7%-9% [BID-QD] and 18%-32% [BID-QD], in BD and ICS patients, respectively) because of failure to meet predetermined asthma stability criteria. Conclusion: The efficacies of FP100BID and FP200QD were comparable with regard to improvement in pulmonary function and asthma stability in BD patients. In ICS patients, asthma control was maintained with FP200QD, whereas FP100BID provided greater improvements in pulmonary function and asthma stability. (J Allergy Clin Immunol 2000;105:1153-61.)