Theophylline in the management of airflow obstruction. 2. Difficult drugs to use,few clinical indications.

The narrow therapeutic index, potential toxicity, and need to monitor plasma concentrations make theophyllines difficult to use. Other drugs provide comparable or better bronchodilator and prophylactic efficacy. In asthma theophyllines should be considered for chronic stable asthma when treatment with optimal doses of inhaled steroids and bronchodilators fails to provide adequate control; for nocturnal asthma; and for prophylaxis and relief of symptoms in children and adults when inhaled treatment cannot be given. In general, theophyllines cannot be recommended for chronic airflow obstruction. A trial of theophylline is reasonable in individual patients whose symptoms remain troublesome despite a trial of steroids and optimal doses of inhaled bronchodilators.     

Diagnosis and treatment of allergic bronchopulmonary aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) is a rare form of asthma that is most common in corticosteroid-dependent asthmatic patients and cystic fibrosis patients. It is caused by an abnormal T-helper class 2 response of the host to Aspergillus antigens. Although signs and symptoms of typical asthma are usually present with ABPA, unusual features such as fever, expectoration of brown plugs, and central bronchiectasis with or without mucoid impaction on chest radiographs may be present. ABPA is important to diagnose because inadequate therapy may lead to permanent lung destruction. Corticosteroids are the drug of choice for ABPA; however, the doses required are often greater than for routine asthma and corticosteroid dependence is not unusual. Azole therapy appears to have an adjunctive role in treatment in terms of improving signs and symptoms of the disease and demonstrating a corticosteroid-sparing effect.     

Maternal and cord plasma cytokine and chemokine profile in pregnancies complicated by asthma

The mechanisms contributing to worsening of asthma during pregnancy have not been well characterized. Both asthma and pregnancy are conditions associated with a skewing of the immune response from T helper (Th) 1 toward a Th2 response. We hypothesise that worsening of asthma during pregnancy may be due to an enhanced production of circulating proinflammatory cytokines and chemokines and this may be modified by the use of inhaled glucocorticoid treatment. Peripheral blood was collected from asthmatic (n = 35) and control non-asthmatic patients (n = 13) in the third trimester (30–37 weeks) of pregnancy. Fetal blood was collected from the umbilical vein of the placenta after delivery from normal (n = 24) and pregnancies complicated by asthma (n = 24). Plasma samples were assayed for IL-6, -8, eotaxin and RANTES using conventional ELISA. In addition, a range of Th1 and Th2 cytokines measured using Luminex system. There were no significant differences in the levels of maternal IL-6, IL-8, eotaxin and RANTES between asthmatics and nonasthmatics. The results of this study suggest that the presence of asthma does not result in an enhanced circulation of Th2 related cytokines and chemokines during the third trimester of pregnancy. Furthermore peripheral blood cytokine concentrations appear unaffected by inhaled glucocorticoid treatment. Cord plasma eotaxin concentrations were increased in pregnancies complicated by asthma, compared with control. This is the first study to show increased eotaxin production in the feto-placental unit of asthmatic pregnancies and may be one mechanism by which allergy susceptibility is increased in the offspring of asthmatic women.     

Measured bronchodilator use in preschool children with asthma.

OBJECTIVE--To investigate how parents use bronchodilator treatment for relief of symptoms when treating their asthmatic preschool children. DESIGN--A commercial electromechanical timer device was attached to a large volume spacer to record the time and date of each use of inhaled bronchodilator over two months. The recorded time and dates were compared with symptoms noted in an asthma diary card. SETTING--Large paediatric teaching hospital in Glasgow. SUBJECTS--29 preschool children with moderately severe asthma attending a specialist paediatric asthma clinic. MAIN OUTCOME MEASURES--Inhaler use measured by the timer device; symptoms and inhaler use recorded by parents in a daily asthma diary. RESULTS--Satisfactory data were obtained in 22 of the 29 children; the median number of study days was 53 (range 18-77). Asthmatic symptoms were recorded on a median of 30 (3-77) days. Bronchodilator was used on a median of 19 (2-73) days, or on 63% (7-100%) of days when symptoms occurred. The median number of puffs used in a day was 1 (range 0-100) and was significantly related to symptom severity in only 14 of the 22 children. In only two of the 22 children was bronchodilator given more frequently than four hourly, and only five children ever used more than 12 puffs a day. CONCLUSIONS--The frequency of parental administration of bronchodilator treatment was variable and not closely related to the parent''s record of symptom severity. Parents often recorded symptoms in their children but did not treat them.     

Using information from asthma patients: a trial of information feedback in primary care.

OBJECTIVE--To test the effects of feedback of information about patients'' asthma to primary care teams. DESIGN--Patients'' reports of morbidity, use of health services, and drug use on questionnaire was given to primary care teams. Randomised controlled trial with general practices as the subject of the intervention was used to test effectiveness of supplying information. SETTING--Primary care in district health authority, London. SUBJECTS--23 general practices, each of which notified at least 20 asthmatic patients aged 15-60 years for each principal. Practices were randomly allocated to an invention group (receiving feedback of information on control of asthma) or a control group (no feedback). INTERVENTION--Information on cards inserted in patients'' medical records; booklet copies of information for team members; formal presentation to primary care teams; poster displays of data on patients in each practice. MAIN OUTCOME MEASURES--Type and frequency of asthma symptoms, use of health services, use of asthma drugs. RESULTS--Reported morbidity at entry to the study was substantial: 45% (818) patients reported breathlessness at least once a week. Less than half these patients were using inhaled steroids regularly. Intervention and control groups did not differ in practice or patient characteristics on entry to the study. In spite of the potential for improvement no differences were observed between the two practice groups at the end of the study--for example, breathlessness at least once a week in last six months was experienced by 36% in intervention group v 35% in control group (t = -0.27, P < 0.79); surgery attendance in last six months by 48% v 48% (t = -0.05, P < 0.96); regular use of inhaled steroids by 60% v 58% (t = 0.51, P < 0.62). CONCLUSION--Feedback to general practitioners of information about patients'' asthma does not on its own lead to change in the outcome of clinical care.     

Lower leukotriene C(4) levels in bronchoalveolar lavage fluid of asthmatic subjects after 2.5 years of inhaled corticosteroid therapy

Long-term treatment with inhaled corticosteroids has been shown to result in improvement of symptoms and lung function in subjects with asthma. Arachidonic acid (AA) metabolites are thought to play a role in the pathophysiology of asthma. It was assessed whether differences could be found in bronchoalveolar lavage (BAL) AA metabolite levels between subjects with asthma who were treated for 2.5 years with inhaled bronchodilators alone or in combination with inhaled corticosteroids. Prostaglandin (PG)D(2), PGF(2alpha), 6-keto-PGF(1alpha), thromboxane B(2), leukotriene (LT)C(4) and LTB(4) levels and cell numbers were assessed in BAL fluid from 22 non-smoking asthmatic subjects. They were participating in a randomized, double-blind multicentre drug trial over a period of 2.5 years. Results of the group treated with inhaled corticosteroids (CS(+): beclomethasone 200 mug four times daily) were compared with the other group (CS(-)) which was treated with either ipratropium bromide (40 mug four times daily) or placebo. BAL LTC(4) levels of asthmatic subjects were significantly lower after 2.5 years inhaled corticosteroid therapy (CS(+), 9(1-17) pg/ml vs. CS(-), 16(6-53) pg/ml; p = 0.01). The same trend was observed for the PGD(2) levels. The results suggest that inhaled corticosteroids may exert their beneficial effect on lung function via a mechanism in which inhibition of LTC(4) synthesis in the airways is involved.     

Induction of drug-metabolizing enzymes and transporters in human bronchial epithelial cells by beclomethasone dipropionate

Inhaled steroids are the most potent anti-inflammatory therapy commonly used in bronchial asthma. There are, however, a small number of asthmatic patients who do not respond to inhaled steroid-treatment. The stimulation of metabolism and excretion of inhaled drugs at bronchial tissues might lead to a decrease in the effect of the drugs, although the molecular mechanism of this resistance is unclear. In this study, we found that beclomethasone dipropionate (BDP) stimulated the expression of mRNAs for uridine 5'-diphosphate glucuronosyl transferase 2B4 and 2B11, and transporters such as multidrug resistance P-glycoprotein, multidrug resistance-associated protein 1 and 2 in cultured bronchial epithelial cells. It is possible that the individual differences of expression of drug metabolizing enzymes and transporters and their enhancement with BDP are implicated in the individual differences of reactivity over steroid medical treatment.     

不同剂量糖皮质激素治疗老年哮喘急性发作的对比研究

目的:探讨不同剂量吸入型糖皮质激素(ICS)治疗老年哮喘急性发作的疗效及安全性分析。方法:将108例老年哮喘急性发作患者随机分为A组(34例)、B组(38例)和C组(36例),分别吸入布地奈德200μg/d、400μg/d、800μg/d;治疗3个月后再随机分为低剂量组(200μg/d,n=)和高剂量组(400μg/d)进行维持治疗,并随访观察12个月。结果:治疗3个月后,三组的临床症状评分、肺功能较治疗前均有显著改善,差异有统计学意义(P<0.05);B组、C组治疗后的临床症状评分、肺功能及症状消失时间均显著优于A组,而B组、C组之间差异无统计学意义(P>0.05);A组和B组不良反应的发生率分别为5.9%,10.5%,显著低于C组30.6%,差异有统计学意义(P<0.05);维持治疗期间,低剂量组复发率为21.2%,高剂量组为20.4%,差异无统计学意义(P>0.05)。结论:老年哮喘急性发作患者给予ICS 400μg/d治疗剂量及200μg/d维持剂量即可取得较好的治疗效果,可减少不良反应,提高患者的耐受性。     

Use of the low-dose corticotropin stimulation test for the monitoring of children with asthma treated with inhaled corticosteroids

OBJECTIVE: Subnormal hypothalamic-pituitary-adrenal (HPA) function and rare cases of adrenal crisis have been reported in asthmatic children treated with inhaled corticosteroids. We investigated subnormal HPA activity and followed up affected patients until recovery of normal HPA functions. STUDY DESIGN: 100 children with persistent asthma underwent low-dose corticotropin testing, with the administration of 1 microg of 1-24 ACTH intravenously. Treatments were beclomethasone dipropionate as a metered-dose inhaler, n = 14, budesonide as a dry-powder inhaler, n = 16, fluticasone propionate as a metered-dose inhaler n = 31 or a dry-powder inhaler n = 39. The mean commercially labelled dose was 520 +/- 29 microg/day (mean +/- SEM, range: 160-1,000) and the equipotent dose (which compares the efficiency of these drugs for treating asthma and their responsibility for systemic effects) was 890 +/- 55 microg/day (range: 200-2,000). RESULTS: The mean stimulated cortisol level +/- SEM (and range) of the patient was 482 +/- 12 (148-801), and that of 40 age-matched controls was 580 +/- 12.5 (439-726), (SD = 79). The result was subnormal (more than 2 SD below the mean of the controls) in28 of the 100 patients. One-four stepwise decreases of 10-100% in the daily equipotent doses received by the patients with abnormal low-dose corticotropin testing results led to normal results in subsequent low-dose corticotropin testing in 27 retested patients. The mean time interval between two tests was 5 months (range: 2-6 months) and the mean period required for normalization of the test was 13 months (range: 2-21). Only one case of asthma exacerbation and no adrenal crisis were observed over these periods. CONCLUSIONS: Decreasing daily equipotent doses led to recovery of normal HPA function without asthma exacerbation. Thus, a revision of the doses of inhaled corticosteroids used in asthmatic children with a progressive decrease to the consensus-recommended doses should decrease the systemic effects of inhaled corticosteroids, while minimizing the risk of asthma exacerbation.     

Domiciliary nebulisers in asthma: a district survey.

Fifty three patients who were found to be using a home nebuliser for asthma completed a questionnaire. The results showed some confusion about the criteria for recommending whether a patient should buy a nebuliser and for its correct use. Twelve patients had not received any instruction on the use of their nebuliser, and only 11 of those old enough used a peak flow meter in conjunction with it. Eight patients aged 7-15 were using inhaled sympathomimetic aerosols only at the time of buying a nebuliser as compared with most of the older patients, who were using regular oral steroids. Forty nine patients assessed their asthma as moderate to severe, but eight of these were not attending a hospital clinic. Several patients were using 20 mg salbutamol or more every day, and on occasion doses of up to 50 mg a day were reported. It is recommended that patients should be assessed before they buy a nebuliser and advice given on correct use by a district nebuliser service, organised either by respiratory function technicians or in physiotherapy departments for adults together with a paediatric health visitor for children.     

Asthma management among allergists in Italy: results from a survey

Background

In Europe more than 50% of asthmatic treated patients have not well-controlled asthma. Asthma affects about 2.5 million of patients in Italy.

Aims and objectives

The present survey aims at investigating how Italian allergists approach asthmatic patients, in order to highlight pitfalls and unmet needs concerning real-life asthma management.

Methods

An anonymous 16 item web questionnaire was available (April–October 2015) to all allergists who visited the web site of SIAAIC (Società Italiana di Allergologia, Asma Immunologia Clinica). Those who wished to give their contribution had the opportunity to answer about epidemiology, risk factors, treatment approaches, and adherence to therapy.

Results

One hundred and seventy four allergists answered the survey. 54% of them reported up to 10 patient visits per week and 35.3% between 10 and 30. The most frequent reasons of follow up visits are routine check-up (56.5% of allergists), and worsening of symptoms (41% of allergists). Nocturnal apnoeas, gastro-esophageal reflux and obesity are the most important comorbidities/risk factors of poorly controlled asthma. Bronchial hyper-responsiveness, increased NO levels and reduced exercise tolerance are the most important indicators of asthma severity. Concerning therapy, ICS combined with LABA is the treatment of choice suitable for the majority of patients. A rapid onset of action and a flexible ICS dosage are indicated as the optimal characteristics for achieving the therapeutic goals. Poor adherence to therapy is an important reason for symptom worsening for the majority of allergists. Complex dosage regimens and economic aspects are considered the most important factors impacting on adherence.

Conclusions

Allergists are involved in the management of asthma, regularly seeing their patients. Co-morbidities are frequent in asthmatic patients and may impact negatively on disease control, thus identifying patients who need a more careful and strict monitoring. Airway hyper-responsiveness to methacholine challenge test and nitric oxide are considered important indicators of asthma severity. The combination of LABA and inhaled steroids is considered the treatment of choice for most asthmatic patients, in keeping with broad evidence indicating that the combination therapy is more effective and rapid in gaining asthma control than inhaled corticosteroids alone. Adherence to medication regimens is considered of essence to achieve the therapeutic goals.

     

Serum levels of total IgE and soluble CD23 in bronchial asthma

The aim of the present study was to compare, during the pollen season, serum levels of total IgE and soluble CD23 (sCD23) from patients with allergic bronchial asthma, with those from healthy subjects. Significantly higher levels of total IgE and sCD23 were found in patients with asthma compared to the control group. Both in normal controls and in asthmatic patients, a significant correlation was shown between the levels of these two molecules. In asthmatic patients, significant correlations were found for both total IgE and sCD23, with lung function measured as bronchial responsiveness to inhaled methacholine. These results suggest that in asthmatic patients, in addition to the study of total serum IgE levels, the assessment of sCD23 serum levels may be helpful in the evaluation of disease activity.     

Asthma due to industrial use of chloramine.

Seven brewery workers developed asthmatic symptoms after using chloramine (chloramine-T) powder as a sterilising agent. They gave positive weal and flare reactions to skin-prick tests with solutions of chloramine at strengths that caused no reactions in unexposed controls. The symptoms did not recur once the men had been removed from areas in which chloramine was handled. As well as causing irritant effects, inhaling dry or liquid aerosols of chloramine may cause sensitisation, with workers being prone to allergic asthma on reexposure. In view of this, measures should be taken to ensure that chloramine is not inhaled.     

II. The late asthmatic responses

Immediate asthmatic responses have been regarded as the characteristic type of asthmatic response to follow exposure to inhaled allergens in patients with extrinsic asthma. They begin within minutes, clear within one to three hours and are inhibited by disodium cromoglycate but not by corticosteroids. They involve the reaction of antigen with antibodies usually of the IgE class. In recent years allergen inhalation tests have demonstrated the frequent occurrence of late asthmatic responses, either following immediate responses (dual responses) or occurring in isolation. The late asthmatic responses begin two to six hours after the allergen challenge, are prolonged and often severe, and are inhibited by both disodium cromoglycate and corticosteroids. The mechanisms involved in their provocation are not clearly understood but from the allergic viewpoint they may involve the participation of IgG ± IgM antibodies and/or IgE antibodies. Late asthmatic responses explain the frequent occurrence of allergen-induced prolonged asthma. Their features suggest that they are more important than immediate responses in the pathophysiology of asthma.     

Corticosteroids: the mainstay in asthma therapy

Inflammation is now marked as a central feature of asthma pathophysiology and aims of current asthma management are not only to treat acute symptoms of wheezing, breathlessness, chest tightness, cough but also to suppress the underlying inflammatory component. Despite the availability of a number of drugs, corticosteroids remain the mainstay in the management of all types of asthma as these are the most potent and effective antiinflammatory agents available so far. Corticosteroids suppress virtually every step in inflammation. However therapeutic doses of oral glucocorticoids are associated with a range of adverse reactions. To overcome these side effects, inhalations have been developed to deliver glucocorticoids directly to the lungs and in the process a number of aerosol preparations have become available, which have advantage of significantly lower toxicity due to low systemic absorption from the respiratory tract and rapid inactivation. Despite considerable efforts by pharmaceutical industry, it has been difficult to develop novel therapeutic agents for asthma management, which could surpass inhaled corticosteroids. Currently the data favours using inhaled corticosteroids as monotherapy in the majority of patients in all kinds of asthma. If combination therapy is recommended to achieve additional control in severe asthma cases, other drugs such as beta-agonists, antileukotrienes, theophylline, etc. are considered as adjunct therapies to corticosteroids. This review discusses the importance of corticosteroids as first line therapy for asthma treatment with the availability of inhaled corticosteroids for chronic treatment and oral formulations for treating acute exacerbations of moderate to severe asthma.     

Relationship of inhibition of prostaglandin biosynthesis by analgesics to asthma attacks in aspirin-sensitive patients.

Eleven patients with asthma and aspirin hypersensitivity have been challenged with eight non-steroidal anti-inflammatory drugs. Each drug was given by mouth in at least three different doses and the patients'' symptoms and peak expiratory flow (PEF) rates were observed over a three-hour period. Indomethacin 5 mg caused bronchoconstriction in all patients. Therapeutic doses of mefenamic or flufenamic acid caused bronchoconstriction in most patients. Phenylbutazone 200-400 mg induced a moderate fall in PEF. There were no reactions to therapeutic doses of salicylamide, paracetamol, benzydamine, and chloroquine. Microsomal prostaglandin synthetase, activity was inhibited by aspirin, indomethacin, mefenamic acid, flufenamic acid, and phenylbutazone. The other four drugs had no inhibitory effect. We suggest that precipitation of attacks in asthmatic patients hypersensitive to certain anti-inflammatory drugs is related to drug''s ability to inhibit prostaglandin biosynthesis.     

Effect of indomethacin on allergen-induced asthmatic responses

Previous studies have suggested that inhibition of the cyclooxygenase pathway of arachidonic acid metabolism may suppress the late asthmatic responses to inhaled allergen. Both human and animal studies have suggested that prostanoids may also be involved in increases in airway responsiveness after ozone and allergen. We studied seven atopic subjects, who had a dual asthmatic response to inhaled allergen, during a control period and then after pretreatment with indomethacin (50 mg) or placebo twice daily for 2 days, administered in a randomized, double-blind manner. Indomethacin had no significant effect on the base-line airway responsiveness to histamine (P = 0.22) or the allergen-induced early or late asthmatic response (P = 0.49). However, indomethacin inhibited the increase in airway responsiveness (express as histamine PC20) after allergen inhalation. The log difference in preallergen to postallergen histamine PC20 was 0.49 +/- 0.08 (SE) during the control period, 0.46 +/- 0.08 (SE) after placebo (P = 0.81), and 0.22 +/- 0.10 (SE) after indomethacin (P = 0.02). Although indomethacin is useful for examining the role of cyclooxygenase products in asthmatic responses, it should not be considered in the treatment of asthma. We conclude that cyclooxygenase products are not significant mediators of allergen-induced early or late asthmatic responses but are involved in the pathogenesis of airway hyperresponsiveness after allergen inhalation.