Purpura associated with hypergammaglobulinemia,renal tubular acidosis and osteomalacia.

Two patients with hyperglobulinemia associated with purpura were studied. One had features of Sjögren''s syndrome, while the other appeared to have a primary condition -- "chronic benign purpura". Both patients also had renal tubular acidosis, osteomalacia and renal calculi, with disturbed calcium metabolism and acid-base balance. Autoantibodies were detected in the serum of both patients, and mononuclear cell infiltrates were noted in skin and kidney biopsies from both.     

Effect of inhaled corticosteroids on episodes of wheezing associated with viral infection in school age children: randomised double blind placebo controlled trial.

OBJECTIVES: To determine the effect of regular prophylactic inhaled corticosteroids on wheezing episodes associated with viral infection in school age children. DESIGN: Randomised, double blind, placebo controlled trial. SETTING: Community based study in Southampton. SUBJECTS: 104 children aged 7 to 9 years who had had wheezing in association with symptoms of upper and lower respiratory tract infection in the preceding 12 months. INTERVENTIONS: After a run in period of 2-6 weeks children were randomly allocated twice daily inhaled beclomethasone dipropionate 200 micrograms or placebo through a Diskhaler for 6 months with a wash out period of 2 months. Children were assessed monthly. MAIN OUTCOME MEASURES: Forced expiratory volume in 1 second (FEV1); bronchial responsiveness to methacholine (PD20); percentage of days with symptoms of upper and lower respiratory tract infection with frequency, severity, and duration of episodes of upper and lower respiratory symptoms and of reduced peak expiratory flow rate. RESULTS: During the treatment period there was a significant increase in mean FEV1 (1.63 v 1.53 1; adjusted difference 0.09 1 (95% confidence interval 0.04 to 0.14); P = 0.001) and methacholine PD20 12.8 v 7.2 mumol/l; adjusted ratio of means 1.7 (1.2 to 2.4); P = 0.007) in children receiving beclomethasone dipropionate compared with placebo. There were, however, no significant differences in the percentage of days with symptoms or in the frequency, severity, or duration of episodes of upper or lower respiratory symptoms or of reduced peak expiratory flow rate during the treatment period between the two groups. CONCLUSIONS: Although lung function is improved with regular beclomethasone dipropionate 400 micrograms/day, this treatment offers no clinically significant benefit in school age children with wheezing episodes associated with viral infection.     

Ozone uptake in the intact human respiratory tract: relationship between inhaled dose and actual dose.

Inhaled concentration (C), minute volume (MV), and exposure duration (T) are factors that may affect the uptake of ozone (O(3)) within the respiratory tract. Ten healthy adult nonsmokers participated in four sessions, inhaling 0.2 or 0.4 ppm O(3) through an oral mask while exercising continuously to elicit a MV of 20 l/min for 60 min or 40 l/min for 30 min. In each session, fractional absorption (FA) was determined on a breath-by-breath basis as the ratio of O(3) uptake to the inhaled O(3) dose. The mean +/- SD value of FA for all breaths was 0.86 +/- 0.06. Although C, MV, and T all had statistically significant effects on FA (P < 0.0001, P = 0.004, and P = 0.026, respectively), the magnitudes of these effects were small compared with intersubject variability. For an average subject, a 0. 05 change in FA would require that C change by 1.3 ppm, MV change by 46 l/min, or T change by 1.7 h. It is concluded that inhaled dose is a reasonable surrogate for the actual dose delivered to a particular subject during O(3) exposures of <2 h, but it is not a reasonable surrogate when comparisons are made between individuals.     

Low incidence of pneumonia in COPD patients treated with inhaled corticosteroids undergoing pulmonary rehabilitation

Background

Based on meta-analyses results, it is currently acknowledged that there is an increased risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD) undergoing inhaled corticosteroids (ICS) treatment. However, this is not found to be true in those with asthma. No data on this risk are available for COPD patients involved in pulmonary rehabilitation program (PR).

Methods

For 1 year, we prospectively studied 2 cohorts of COPD patients—undergoing PR and not undergoing PR. The first group included 438 patients undergoing PR of which 353 were treated with ICS, and 85 were treated with bronchodilators only. The second group was comprised of 76 COPD patients who were treated with ICS, but not PR. The control group consisted of 49 ICS-treated patients with asthma. The diagnosis of pneumonia, when suspected, had to be confirmed with a chest x-ray.

Results

Overall, 6 cases of pneumonia were diagnosed in the first study group: 5 ICS-treated patients and 1 patient treated only with bronchodilators. This corresponded to a rate of 1.41 and 1.17%, respectively, compared to a rate of 6.6% in COPD patients not treated with PR, which was significantly higher (p?=?0.029) than that in the first study group. No case of pneumonia was registered among patients with asthma.

Conclusions

These findings suggest that a significantly lower incidence of pneumonia is found in COPD patients treated with ICS and PR than in patients treated with ICS but not with PR. This observation deserves to be investigated in large populations of PR-treated COPD patients, possibly in multi-centric cohort studies.

     

Predictors of clinical response to extrafine and non-extrafine particle inhaled corticosteroids in smokers and ex-smokers with asthma

We performed a post-hoc analysis of the OLiVIA-study investigating whether current and ex-smoking asthmatics with small airways dysfunction (SAD) show a better response in airway hyperresponsiveness (AHR) to small particle adenosine after treatment with extrafine compared to non-extrafine particle inhaled corticosteroids (ICS), and to investigate which clinical parameters predict a favorable response to both treatments. We show that smoking and ex-smoking asthmatics with and without SAD have a similar treatment response with either extrafine or non-extrafine particle ICS. We also found that lower blood neutrophils are associated with a smaller ICS-response in smokers and ex-smokers with asthma, independent from the level of blood eosinophils.     

Design and synthesis of long acting inhaled corticosteroids for the treatment of asthma

In this Letter we present data for a novel series of ICS for the treatment of asthma. 'Inhalation by design' principles have been applied to a series of highly potent steroidal GR agonists, with a focus on optimising the potential therapeutic index in human. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimise systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance as well as glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimise drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity and solubility were considered to ensure compatibility with a dry powder inhaler. This work culminated in the identification of the clinical candidate 15, which demonstrates preclinically the desired efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of asthma.     

Withdrawal of inhaled corticosteroids in individuals with COPD - a systematic review and comment on trial methodology

Inhaled corticosteroids (ICS) reduce COPD exacerbation frequency and slow decline in health related quality of life but have little effect on lung function, do not reduce mortality, and increase the risk of pneumonia. We systematically reviewed trials in which ICS have been withdrawn from patients with COPD, with the aim of determining the effect of withdrawal, understanding the differing results between trials, and making recommendations for improving methodology in future trials where medication is withdrawn. Trials were identified by two independent reviewers using MEDLINE, EMBASE and CINAHL, citations of identified studies were checked, and experts contacted to identify further studies. Data extraction was completed independently by two reviewers. The methodological quality of each trial was determined by assessing possible sources of systematic bias as recommended by the Cochrane collaboration. We included four trials; the quality of three was adequate. In all trials, outcomes were generally worse for patients who had had ICS withdrawn, but differences between outcomes for these patients and patients who continued with medication were mostly small and not statistically significant. Due to data paucity we performed only one meta-analysis; this indicated that patients who had had medication withdrawn were 1.11 (95% CI 0.84 to 1.46) times more likely to have an exacerbation in the following year, but the definition of exacerbations was not consistent between the three trials, and the impact of withdrawal was smaller in recent trials which were also trials conducted under conditions that reflected routine practice. There is no evidence from this review that withdrawing ICS in routine practice results in important deterioration in patient outcomes. Furthermore, the extent of increase in exacerbations depends on the way exacerbations are defined and managed and may depend on the use of other medication. In trials where medication is withdrawn, investigators should report other medication use, definitions of exacerbations and management of patients clearly. Intention to treat analyses should be used and interpreted appropriately.     

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.