Anti-inflammatory Treatment For Asthma Research Articles

Anti inflammatory treatment for asthma (BSACI session)

Anti inflammatory treatment for asthma (<i>BSACI session</i>)

Eosinophils and eosinophilic cationic protein in induced sputum and blood: effects of budesonide and terbutaline treatment

There is a need for easily measurable markers of airway inflammation to guide the use of anti-inflammatory treatment in asthma. Eosinophilic cationic protein (ECP) levels in sputum and blood correlate with clinical severity, and serial measurements of ECP have been proposed as a suitable candidate. Our aim was to confirm that sputum and serum ECP measurements would provide a more sensitive indicator of responses to asthma treatment than eosinophil counts per se, in a randomized, placebo-controlled, crossover study of terbutaline, budesonide, and their combination in patients with chronic persistent asthma. We compared the changes in eosinophil counts and ECP in induced sputum and blood during each treatment period. Budesonide and combined treatment caused a significant reduction in sputum eosinophils (-2.7% and -2.3%, respectively, P < 0.05). Sputum eosinophils increased with terbutaline (+3.9%, P = 0.049). In contrast, the changes for sputum ECP were not significant. There was a similar treatment effect on blood eosinophils, but not for serum ECP. Correlations between sputum and blood eosinophils were significant with and without budesonide, but were nonsignificant between sputum and blood ECP during the active treatments. Correlations between sputum eosinophils and ECP, and between blood eosinophils and serum ECP were greatest during treatment with placebo or terbutaline alone: budesonide weakened or abolished these relationships. Compared with eosinophil counts, ECP measurements in either induced sputum or serum failed to reflect treatment-related changes in chronic asthma. We conclude that ECP is not a sensitive or reliable means of evaluating airway inflammation, and can not be recommended for assessing responses to anti-inflammatory therapy.

Effects of budesonide and formoterol on eosinophil activation induced by human lung fibroblasts.

Budesonide and formoterol are extensively used in current asthma therapy. Budesonide is known as potent antiinflammatory agent and formoterol also appears to have some antiinflammatory properties. We investigated inhibitory effects of these drugs on eosinophil activation in vitro as induced by fibroblast-conditioned medium (FCM). We measured the modulation of expression of clonal designator (CD)11b and L-selectin with flow cytometry after 4 h or 16 h of culture of eosinophils when budesonide or formoterol was applied either directly to the eosinophils while they were stimulated with FCM (direct method) or when each drug was applied to lung fibroblasts from which conditioned medium was then administered to eosinophils (indirect method). In the direct method, budesonide (10(-)(8) M) inhibited the modulation of CD11b (44 [25th to 75th percentiles: 26 to 66]% of control) and L-selectin (30 [-13 to 48]% of control) only after 16 h, and not after 4 h. Formoterol did not directly inhibit the modulation of eosinophil CD11b and L-selectin expression. In the indirect method, both budesonide and formoterol inhibited lung fibroblast activation, resulting in diminished eosinophil activation after 4 h. Budesonide or formoterol at 10(-)(8) M inhibited upregulation of CD11b to 26 [15 to 40]% and 38 [23 to 46]%, respectively, and inhibited L-selectin shedding to 14 [-3 to 50]% and 27 [2 to 62]%, respectively, of control values. These results show that budesonide inhibits eosinophil activation primarily through effects on lung fibroblasts, presumably by inhibiting production of granulocyte-macrophage colony-stimulating factor. After longer incubation periods, budesonide also directly inhibits eosinophil activation. In contrast, formoterol can inhibit eosinophil activation only via inhibitory effects on lung fibroblasts. We did not observe an additional effect of formoterol, beyond the effects induced by budesonide under any circumstance studied. Lung fibroblasts, in addition to eosinophils, may serve as important target cells for antiinflammatory treatment in asthma.

ALTERNATIVE ANTI-INFLAMMATORY AND IMMUNOMODULATOR MEDICATIONS FOR ASTHMA

The National Institutes of Health (NIH) 1997 Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma 12 (EPR2) proposes a standard of care for patients with this chronic, predominantly eosinophilic, inflammatory disease: that patients with mild persistent asthma be treated with daily low-dose inhaled corticosteroids, that patients with moderate persistent asthma receive higher doses of inhaled corticosteroids, and that patients with severe persistent asthma be treated with the highest doses of inhaled corticosteroids, long-acting bronchodilators, and the lowest doses of oral corticosteroids that can achieve the therapeutic goal. The EPR2 suggests other medications as add-on therapy or as alternatives. This article reviews randomized clinical trials that address alternative medications for the management of persistent asthma in patients who require daily treatment. When available, head-to-head comparisons are discussed. Traditionally, alternative anti-inflammatory treatments for asthma are given to patients with severe disease that requires higher doses of oral corticosteroids for control of symptoms. The experience of rheumatologists treating patients with arthritis has led to the suggestion that methotrexate, gold salts, hydroxychloroquine, dapsone, and cyclosporin may be of benefit for severe steroid-dependent asthmatic patients. In contrast, for patients with mild to moderate persistent asthma, alternative medications with potential anti-inflammatory effect include cromolyn sodium, nedocromil, theophylline, and the leukotriene modifiers. Several of these agents, as well as long acting oral and inhaled bronchodilators, have also been proposed as effective means to reduce the daily dose of the inhaled corticosteroid while maintaining or improving control of asthma. Outcome parameters vary among studies. The most common objective measures include forced expiratory volume in 1 second (FEV 1 ), peak expiratory flow rate (PEFR), and measures of bronchial hyperreactivity. Dosage levels of oral corticosteroids taken for asthma, albuterol use, and level of symptom control are also reported indicators of efficacy. The adverse drug profile of each therapy needs to be considered. Most clinical studies unfortunately are short-term, and many of the potential safety concerns may appear only after several years of treatment. Study populations, even when controlled for disease severity, differ among clinical investigations and make comparative analysis difficult. Randomized clinical trials of two or more therapies provide the best comparisons. In analyzing the outcomes of alternative medications, one needs to consider the placebo effect on clinical changes. Many clinical trials have demonstrated that enrollment alone can improve lung function and symptom control. In placebo-controlled trials, a clinically significant difference, not just a statistical difference, needs to be demonstrated.

Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils, and exhaled nitric oxide levels in patients with asthma

BACKGROUNDAirway 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...

Vascularity in asthmatic airways: relation to inhaled steroid dose.

There is an increase in vascularity in the asthmatic airway. Although inhaled corticosteroids (ICS) are an effective anti-inflammatory treatment in asthma, there are few data on any effects on structural changes. Endobronchial biopsy specimens from seven asthmatic subjects not receiving ICS and 15 receiving 200-1500 microg/day beclomethasone dipropionate (BDP) were immunohistochemically stained with an anti-collagen type IV antibody to outline the endothelial basement membrane of the vessels. These were compared with biopsy tissue from 11 non-asthmatic controls (four atopic and seven non-atopic). There was a significant increase in the density of vessels (number of vessels/mm2 of lamina propria) in the asthmatic subjects not on ICS compared with non-asthmatic controls (mean 485 (interquartile range (IQR) 390-597) versus 329 (IQR 248-376) vessels/mm2, p<0.05; 95% CI for the difference 48 to 286). There was no significant difference between asthmatic subjects on ICS and those not on ICS or control subjects in the number of vessels/mm2 (mean 421 (IQR 281-534)). However, patients who received >/=800 microg/day BDP tended to have a reduced number of vessels/mm2 compared with patients not on ICS and those receiving </=500 microg/day BDP (mean 366 (IQR 153-608) versus 494 (IQR 391-583), p = 0.08; 95% CI for the difference -31 to 288). Similarly, there was an increase in the percentage of lamina propria occupied by vessels in asthmatic patients not on ICS compared with controls (mean 15.6% (IQR 13.1-18.0) versus 10.1% (IQR 8.4-13.3), p<0.01; 95% CI for the difference 2.4 to 9.3) but a significant decrease in the percentage of lamina propria occupied by vessels was detected in asthmatic patients on ICS (mean 11.4% (IQR 9.1-14.9), p<0.01; 95% CI for the difference 0.7 to 7.7) compared with those not on ICS. The density of vessels correlated significantly with both airway hyperresponsiveness and percentage change in forced expiratory volume in one second (FEV1) after bronchodilator (r = -0. 38 for PD20 methacholine and r = 0.49 for change in percentage FEV1 after bronchodilator versus number of vessels/mm2, p<0.05). These findings suggest that ICS, especially at higher doses, may reduce airway wall vascularity in asthmatic subjects but further longitudinal intervention studies are required to confirm this suggestion.

How Does Auranofin Compare with Methotrexate and Cyclosporin as a Corticosteroid-Sparing Agent in Severe Asthma?

Despite optimal anti-inflammatory treatment of asthma, including use of high dosage, high potency inhaled corticosteroids, a subset of corticosteroid-dependent patients require substantial amounts of daily systemic corticosteroids for adequate control. Several anti-inflammatory modulating agents (auranofin, methotrexate and cyclosporin) have been evaluated for their corticosteroid-sparing properties under such circumstances. This analysis was gleaned primarily from randomised, double-blind, placebo-controlled trials of these agents. Global assessment of corticosteroid-sparing efficacy of these drugs revealed an advantage of auranofin over both methotrexate and cyclosporin. In addition, the comparative adverse event profiles of these drugs indicated that auranofin exhibited milder, more tolerable adverse effects. Therefore, auranofin presents a better risk : benefit option in initial attempts to wean dependent patients from corticosteroids.

Effects of long-term use of high-dose inhaled steroids on bone density and calcium metabolism

Background: Inhaled steroids are the mainstay in the antiinflammatory treatment of asthma. In the last few years, these agents have been used in increasing doses. Because high doses of inhaled steroids can reduce serum osteocalcin levels, there are concerns regarding their long-term effects on bone metabolism. Methods: We examined the effects of doses of 800 μg/day or greater of beclomethasone or budesonide for more than 18 months in 37 asthmatic subjects (group A), matched to a control group of 37 asthmatic subjects using little or no inhaled steroids (<500 μg, group B). All had a clinical evaluation, measurements of expiratory flows, and determination of serum creatinine, calcium, phosphate, γ-glutamyl transpeptidase, alkaline phosphatase, cortisol, and osteocalcin levels. A 2-hour urinary sample was obtained for creatinine, calcium, phosphate, hydroxyproline, and cortisol measurements. Bone density was assessed at the lumbar spine level and at the hip with a Hologic-QDR-2000 osteodensitometer (Hologic, Boston, Mass.). Results: The mean (±SD) daily dose of inhaled steroids over the last 2 years was 1140 ± 353 μg in group A (mean duration of use of >800 μg/day, 34.2 ± 13.0 months) and 89 ± 98 μg for group B (mean duration of use of <500 μg/day, 15.7 ± 18.8 months). The number of oral steroid treatments (<15 days) during the last 2 years was small in the two groups, 0.92 ± 1.27 in group A and 0.05 ± 0.23 in group B ( p > 0.05). The only differences between our two groups in terms of serum or urinary parameters were for mean osteocalcin level, which was lower in group A (2.16 ± 1.09 ng/ml) than in group B (2.70 ± 0.98 ng/ml) ( p = 0.029), and in mean urinary phosphorous level, which was higher in group A (1.44 ± 0.76 mmol/2 hr) than in group B (1.26 ± 0.89 mmol/2 hr ( p = 0.034). Mean urinary hydroxyproline levels were 15.51 ± 6.98 μmol/2 hr in group A and 13.53 ± 7.13 μmol/2 hr in group B ( p > 0.05). Mean mineral bone densities of the lumbar spine and hip were similar in the two groups with values of 0.923 ± 0.136 gm/cm 2 and 0.719 ± 0.147gm/cm 2 in group A and 0.933 ± 0.154 gm/cm 2 and 0.694 ± 0.095 gmlcm 2 in group B ( p > 0.05). The T and Z scores for lumbar spine were − 1.32 ± 1.22 and −0.85 ± 1.02 in group A and −1.19 ± 1.33 and −0.72 ± 1.08 in group B ( p > 0.05). There was no correlation between the duration or dose of steroid use and bone density or osteocalcin. Although the serum osteocalcin level was lower in the group of subjects using high-dose inhaled steroids, suggesting an osteoblastic depression, bone density was not significantly different compared with the control group. Conclusions: This study shows that although the serum osteocalcin level was lower and the urinary phosphorus level was higher in subjects using high-dose inhaled steroids for a mean of 34 months, compared with a control group, no significant difference in bone density or other markers of bone metabolism was found between the two groups.

Asthma as an inflammatory disease: clinical perspectives.

Asthma is characterised by a persistent, ongoing airway submucosal inflammatory process which may underlie bronchial hyperresponsiveness and airways obstruction. Indirect assessment of airway inflammation includes examination of sputum or serum for eosinophils or eosinophil-derived products, but examination of bronchial mucosal biopsies or bronchoalveolar lavage fluid or cells remains the gold standard. Lymphocyte and eosinophil activation, with the release of certain cytokines such as interleukin-5, lipid mediators such as leukotrienes and eosinophil products such as major basic protein, may be important mechanisms of inflammation in asthma. Less invasive indirect measures of submucosal inflammation are needed to assess the impact of asthma treatment in the clinic. Antiinflammatory treatment in asthma should be introduced as early as possible. A greater understanding of the inflammatory mechanism or of the actions of corticosteroids may lead to the development of more effective and safer drugs for asthma.