Relation between exhaled carbon monoxide levels and clinical severity of asthma

Carbon monoxide (CO) can be detected in exhaled air and is increased in asthmatic patients not treated with corticosteroids. However, it is uncertain whether exhaled CO is related to severity of asthma. To study whether exhaled CO is related to severity of asthma in clinical courses, exhaled CO concentrations were measured on a CO monitor by vital capacity manoeuvre in 20 mild asthmatics treated with inhaled beta2-agonists alone, 20 moderate asthmatics treated with inhaled corticosteroids, and 15 stable asthmatics treated with high dose inhaled corticosteroids and oral corticosteroids once a month over 1 years. Exhaled CO concentrations were also measured in 16 unstable severe asthmatics who visited the hospital every 7 or 14 days for treatment with high dose inhaled corticosteroids and oral corticosteroids. The mean values of exhaled CO in severe asthma over 1 year were 6.7 +/- 9.5 p.p.m. (n = 31, mean +/- SD) and significantly higher than those of non-smoking control subjects (1.2 +/- 0.9 p.p.m., n = 20, P < 0.01). Exhaled CO concentrations in unstable severe asthmatics were significantly higher than those in stable severe asthmatics. However, exhaled CO concentrations in mild and moderate asthmatics did not differ significantly from those in non-smoking control subjects (P > 0.20). There was a significant relationship between the exhaled CO concentrations and forced expiratory volume in one second in all asthmatic patients. These findings suggest that exhaled CO concentrations may relate to the severity of asthma and measurements of exhaled CO concentrations may be a useful means of monitoring airway inflammation in asthma.     

The influence of inhalative corticosteroids on circulating Nerve Growth Factor, Brain-Derived Neurotrophic Factor and Neurotrophin-3 in allergic asthmatics

BACKGROUND: The neurotrophins Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin (NT)-3 are produced, stored and released by various immunological cells. The influence of NTs upon the function of these cells is described. Elevated plasma levels were found in inflammatory, autoimmune and allergic diseases with the highest levels in allergic asthma. A connection between bronchial hyper-responsiveness and serum levels has been reported. OBJECTIVE: Little is known about the influence of treatment with inhaled corticosteroids (ICS) on serum NT levels and their influence on the asthmatic state. METHODS: Eighty-seven volunteers were studied. Thirty-eight were stable allergic asthmatics with constant ICS doses, 29 were asthmatics not receiving anti-asthmatic treatment and 20 were age- and sex-matched healthy controls. Demographic and lung function data were evaluated. NT serum levels were determined by ELISA. RESULTS: NGF and BDNF levels were significantly increased in untreated asthmatics compared to the control and the treated group, while NT-3 demonstrated significantly higher levels in treated asthmatics compared to healthy controls. After stabilization of untreated subjects with ICS, the NT levels decreased significantly. CONCLUSIONS: These results suggest that NTs participate in allergic inflammation and asthma. Effective treatment leads to a decrease of circulating neurotrophic factors.     

Immuno-regulatory cytokines in asthma: IL-15 and IL-13 in induced sputum

BACKGROUND: The importance of Th2-type lymphocyte function in asthmatic airway inflammation is well recognized, but less is known about the factors which regulate the function of these lymphocytes in asthma. The macrophage-derived cytokine, interleukin (IL)-15 has a number of T cell regulatory properties which might be of relevance to asthma and its treatment. OBJECTIVE: The aims were to identify and quantify the T cell regulatory cytokine IL-15 in induced sputum samples from asthmatic patients, in comparison with IL-13, and to relate the levels of these cytokines to treatment with inhaled steroids. METHODS: Induced sputum was collected from 16 asthmatics (eight steroid and eight non-steroid treated) and eight normal controls. IL-15 and IL-13 levels were measured by enzyme-linked immunoassay (ELISA) in sputum. IL-15 levels were also measured in sputum cell culture supernatants and localized to specific sputum cells by immuno-cytochemistry. RESULTS: IL-15 levels were increased and IL-13 levels were decreased in sputum fluid from steroid-treated compared with non-steroid-treated asthmatics. IL-15 was localized specifically to macrophages and the proportion of these cells expressing IL-15 correlated with sputum fluid IL-15 and IL-15 levels in cell culture supernatants, and all were higher in the steroid-treated asthmatics. CONCLUSION: IL-15 and IL-13 production appears to be reciprocally regulated by steroid therapy in asthma patients. The steroid-associated increase in IL-15 may regulate a fundamental shift away from an inflammatory Th2-type environment in asthma and may be an essential component of the cytokine modulation underlying the therapeutic benefit of corticosteroids in this condition.     

Butterbur, a herbal remedy, confers complementary anti-inflammatory activity in asthmatic patients receiving inhaled corticosteroids

BACKGROUND: The effects of butterbur (BB), a herbal remedy, as add-on therapy to inhaled corticosteroids in patients with atopic asthma is currently unknown. OBJECTIVE: We evaluated the effects of BB, given as add-on therapy to asthmatic patients maintained on inhaled corticosteroids, assessing adenosine monophosphate (AMP) bronchoprovocation (primary outcome variable) along with other surrogate inflammatory markers such as exhaled nitric oxide, serum eosinophil cationic protein and peripheral blood eosinophil count. METHODS: Sixteen atopic asthmatic patients with mean (standard error of mean) forced expiratory volume in 1 s (FEV1) of 78 (4)% predicted, maintained on their constant dose of inhaled corticosteroids throughout the study, received twice daily for 1 week either BB 25 mg or placebo (PL), in a double-blind, cross-over fashion, with a 1-week washout period prior to each randomized treatment. Measurements were made at baselines prior to each randomized treatment and following the randomized treatment period. RESULTS: Baseline values for the primary and secondary outcomes were not significantly different prior to BB and PL. AMP provocative concentration causing a 20% reduction from baseline FEV1 (PC20) as doubling dilution change from baseline, significantly improved (P<0.05) with BB, 0.6 (0.2), compared with PL, -0.1 (0.3); a 0.7 doubling dilution difference. Exhaled nitric oxide as change from baseline was significantly reduced (P<0.05) with BB, -1.2 (0.8) p.p.b., compared with PL, 0.5 (0.4) p.p.b. Both serum eosinophil cationic protein and peripheral blood eosinophil count as change from baseline were also significantly suppressed (P<0.05) with BB, -3.9 (3.3) microg/L, -31 (28)x106/L compared with PL, 3.3 (2.5) microg/L, 38 (16)x106/L, respectively. CONCLUSION: Chronic dosing with BB conferred complementary anti-inflammatory activity in atopic asthmatic patients maintained on inhaled corticosteroids. Further studies are now required to assess the potential role for BB as either monotherapy in milder patients or add-on therapy in more severe asthmatics.     

Rhinosinusitis in severe asthma

BACKGROUND: Chronic rhinosinusitis is a common comorbidity of asthma. However, sinonasal involvement in severe steroid-dependent asthma is still undefined. OBJECTIVE: The aim of the study was to evaluate chronic rhinosinusitis in 35 patients with severe steroid-dependent asthma by using a clinical score and coronal computed tomography (CT) scanning. METHODS: Thirty-five subjects (16 female subjects) with severe asthma requiring daily doses of oral corticosteroids were compared with 34 patients (19 female patients) with mild-to-moderate asthma. Sinonasal involvement was studied by using clinical and CT scores. Airflow obstruction, therapy requirement, and asthma triggering factors were carefully assessed. RESULTS: The proportion of patients with symptoms of rhinosinusitis was similar in both groups of asthmatic subjects (74% in patients with severe steroid-dependent asthma and 70% in patients with mild-to-moderate asthma). All subjects with steroid-dependent asthma versus 88% of subjects with mild-to-moderate asthma had abnormal CT scan results. The clinical (P <.05) and CT scan (P <.0005) severity scores were higher in the subjects with severe steroid-dependent asthma. In both groups the CT scan scores were correlated to the clinical scores (P <.0001 and P <.006), but only in the mild-to-moderate group were both scores correlated with high significance (P <.002 and P <.0005) to the absolute number of blood eosinophils. CONCLUSION: Frequency of rhinosinusitis in patients with mild-to-moderate or severe steroid-dependent asthma is similar; however, sinonasal involvement, as evaluated by clinical symptoms and CT scan imaging, is significantly greater in the patients with severe steroid-dependent asthma than in those with mild-to-moderate asthma.     

Features of severe asthma in school-age children: Atopy and increased exhaled nitric oxide

BACKGROUND: Children with severe asthma have persistent symptoms despite treatment with inhaled corticosteroids (ICSs). The differentiating features of severe asthma in children are poorly defined. OBJECTIVE: To identify features of severe versus mild-to-moderate asthma in school-age children using noninvasive assessments of lung function, atopy, and airway inflammation. METHODS: A total of 75 children (median age, 10 years) with asthma underwent baseline characterization including spirometry and lung volume testing, methacholine bronchoprovocation, allergy evaluation, and offline measurement of exhaled nitric oxide (F(ENO)). Twenty-eight were followed longitudinally over 6 months. Participants were assigned to the severe asthma subgroup if they required high-dose ICS plus 2 or more minor criteria. RESULTS: Children with severe versus mild-to-moderate asthma had more symptoms, greater airway obstruction, more gas trapping, and increased bronchial responsiveness to methacholine. Subjects with severe asthma also had higher concentrations of F(ENO) and significantly greater sensitization to aeroallergens. With long-term study, both the reduction in FEV(1) and increase in F(ENO) persisted in the severe versus mild-to-moderate group. Furthermore, despite adjustments in ICS doses, the frequency of exacerbations was significantly higher in subjects with severe (83%) versus mild-to-moderate asthma (43%). CONCLUSION: Severe asthma in childhood is characterized by poor symptom control despite high-dose ICS treatment and can be differentiated from mild-to-moderate asthma by measurement of lung function and F(ENO). CLINICAL IMPLICATIONS: Clinicians should suspect severe asthma in children with poor response to ICS, airway obstruction, and high F(ENO).     

Enhanced frequencies of CD14++CD16+, but not CD14+CD16+, peripheral blood monocytes in severe asthmatic patients

CD16+ monocytes are expanded in various inflammatory conditions. Recently it was reported that CD16+ monocytes can be divided into two subsets with contrasting potential of modulating inflammatory responses, namely CD14++CD16+ and CD14+CD16+ monocytes. Here, we characterized and quantified CD14++CD16+ and CD14+CD16+ monocyte subsets in asthmatic patients in the context of severity of disease and different treatment options. Subjects included seventeen severe asthmatics and eighteen moderate asthmatics treated with moderate-to-high doses of inhaled glucocorticosteroids (GCS), twenty nine steroid-naive mild asthmatics and fifteen healthy controls.First, we demonstrated that CD14++CD16+ monocytes, in contrast to CD14+CD16+ monocytes, present significantly higher expression of anti-inflammatory molecule CD163. The frequency of CD14++CD16+, but not CD14+CD16+ monocytes, was significantly higher in patients with severe asthma as compared to mild and moderate asthmatics. However, the frequency of both CD16+ monocyte subsets did not correlate directly with exhaled nitric oxide levels. Short-term administration of oral GCS in patients with exacerbations resulted in a preferential decrease of CD14+CD16+ monocytes. Our study indicates that CD14++CD16+ and CD14+CD16+ monocyte subsets in asthmatics are differentially modulated by both the inflammatory process and GCS treatment.     

Increased levels of vascular endothelial growth factor in induced sputum in asthmatic patients

BACKGROUND: Vascular endothelial growth factor (VEGF) is highly expressed in the airway of asthmatic patients. As VEGF increases airway vascular permeability, consequent thickening of the airway wall mucosa may lead to narrowing of the airway lumen. OBJECTIVE: We evaluated the relationship between VEGF levels in induced sputum and eosinophilic inflammatory profiles, and the degree of airway vascular permeability in asthmatic patients and we evaluated the effect of inhaled corticosteroids on VEGF levels in induced sputum. METHODS: Induced sputum specimens were obtained from 28 glucocorticosteroids free asthmatics and 11 healthy control subjects. We examined VEGF levels and airway vascular permeability index in induced sputum. After the initial sputum induction, 21 asthmatics received 8-week inhaled beclomethasone dipropionate (BDP, 800 micro g/day) therapy, then sputum induction was repeated. RESULTS: The VEGF levels in asthmatics were significantly higher than in healthy control subjects (P < 0.0001). The VEGF levels were negatively correlated with forced expiratory volume of 1 s (FEV1, % predicted, r = - 0.68, P < 0.001), the percentage of eosinophils (r = 0.51, P < 0.01) and ECP levels (r = 0.39, P < 0.05). Moreover, the VEGF levels were significantly correlated with airway vascular permeability index (r = 0.61, P < 0.001). After 8-week inhaled BDP therapy, the VEGF levels were significantly decreased compared to pretreatment levels (P < 0.0001) and the VEGF levels were significantly correlated with airway vascular permeability index even in post-treatment asthmatics (r = 0.62, P < 0.01). CONCLUSION: The VEGF levels in induced sputum were increased in asthmatics and its levels were associated with degree of airway narrowing and airway vascular permeability. These findings provide strong evidence that VEGF may play an important role in the pathogenesis of bronchial asthma.     

Expression of respiratory mucins in fatal status asthmaticus and mild asthma

AIMS: The airways of patients with asthma are characterized by chronic inflammatory changes comprising mainly T-cells and eosinophils, and airway remodelling with goblet cell metaplasia and submucosal gland hyperplasia. Mucus hypersecretion is often a marked feature, particularly in status asthmaticus. The matrix of airway sputum consists of high molecular glycoproteins and mucins. In this study, the expression and distribution of the major gel-forming mucins MUC5AC and MUC5B were studied in fatal status asthmaticus tissues and bronchial biopsies of mild asthmatic patients. The effect of inhaled corticosteroids on the expression of these mucins was also investigated. METHODS AND RESULTS: Polyclonal antibodies specific for MUC5AC and MUC5B, and a monoclonal antibody for MUC5B were used to stain lung tissues and airway mucosal biopsies obtained from patients who died of status asthmaticus (n=5) and from mild asthmatics (n=4), respectively. Immunohistochemistry for MUC5AC revealed abundant staining of goblet cells situated in the epithelial surface lining and glandular ducts of tissues from patients with fatal asthma. MUC5B immunoreactivity was restricted to mucous cells of submucosal glands and to epithelial cells. In mild asthmatics, large amounts of MUC5B, but not MUC5AC, positive extracellular mucus was found in the airway lumen as plugs, adjacent to the epithelial lining and in the necks of glandular secretory ducts of mild asthmatics. The distribution of MUC5AC and MUC5B in bronchial biopsies of mild asthmatics was similar before and after inhaled steroid treatment. CONCLUSIONS: The expression of MUC5AC and MUC5B shares a similar distribution to normal airways in different states of asthma. The distribution is not affected by topical corticosteroid therapy.     

Chemotactic activity of neutrophils to fMLP and IL-8 in patients with severe asthma with reversible and irreversible airflow obstruction and in patients with chronic obstructive pulmonary disease

Asthma is a chronic inflammatory disease of the airways in which many cell types play a role. Although the most important cells are eosinophils, there are suggestions that also neutrophils may play a role in asthma. The aim of the study was to measure and compare chemotactic activity of neutrophils in patients with severe asthma and with COPD. We examined 49 patients with severe asthma and 23 patients with COPD. The mean number of neutrophils in peripheral blood of 20 asthmatics with irreversible airflow obstruction was 3.96 x 10(6)/ml. The chemotactic activity of neutrophils to FMLP was 2.69 SEM +/- 0.4, to IL-8 in concentration 10-7 microg/ml - 1.64, SEM +/- 0.2, and to IL-8 in concentration 10-8 microg/ml - 1.17, SEM +/- 0.1. The mean number of neutrophils in 29 asthmatics with reversible airflow obstruction was 3.08 x 10(6)/ml. Their chemotactic activity to fMLP was 1.7, SEM +/- 0.1 to IL-8 in concentration 10-7 microg/ml - 1.51. SEM +/- 0.2, and to IL-8 in concentration 10-8 microg/ml - 1.08, SEM +/- 0.1. The mean number of neutrophils in COPD patients was 4.05 x 10(6)/ml and their chemotactic activity to FMLP was 1.9, SEM +/- 0.1 to IL-8 - 1.35, SEM +/- 0.1. All asthmatic patients were treated with inhaled corticosteroids and some of them with oral corticosteroids. Despite of that treatment the number of neutrophils isolated from patients with asthma with irreversible airflow obstruction was almost the same like in COPD patients and chemotactic activity of neutrophils in this group was the highest. We concluded that corticosteroids treatment did not diminished chemotactic activity of neutrophils isolated from patient suffering from asthma with irreversible airflow obstruction.     

Levels of soluble IL-2 receptor in plasma from asthmatics. Correlations with blood eosinophilia, lung function, and corticosteroid therapy.

Evidence now suggests that eosinophils and T lymphocytes infiltrating bronchial tissues may play a key role in the pathophysiology of asthma. Circulating eosinophils, lung function, and plasma soluble IL-2 receptor (sIL-2R) were measured in 42 asthmatic patients referred for symptomatic asthma. The patients were divided into two groups based on the presence or absence of atopy. The group of non-atopic asthmatics was further divided according to the patients' requirement for long term oral corticosteroids. The mean sIL-2R +/- s.d. was 36.3 +/- 9.9 pM in the control group, 28.9 +/- 9.2 pM in the atopic asthmatics, 43.3 +/- 18.07 pM in the non-atopic asthmatics without oral steroid therapy, but was increased in the steroid-treated group (62.2 +/- 19.3 pM, P less than 0.01). A significant correlation was found between FEV1 and circulating eosinophils in atopic asthmatics and in non-atopic asthmatics without oral corticosteroid therapy, but not in the steroid-treated group. Furthermore, significant correlations were found between sIL-2R and FEV1, and between sIL-2R and blood eosinophils, in the group of non-atopic asthmatics not on oral steroid therapy. No such correlations were evidenced in the other groups of asthmatics. Similar results were obtained during the clinical course of three non-atopic patients followed for more than 1 year. These data suggest that T cell activation appears more prominent in non-atopic asthma than in atopic asthma. Moreover, it appears that T cell activation can occur in severe forms of asthma despite steroid treatment. Finally, the results suggest a possible link between T cell activation, eosinophils, and lung function, which may reflect a particular pathogenetic mechanism involved in non-atopic asthma.     

Steroid-sparing effect of subcutaneous SQ-standardised specific immunotherapy in moderate and severe house dust mite allergic asthmatics

BACKGROUND: The present study evaluated the steroid-sparing effect of subcutaneous SQ-standardized specific immunotherapy (SIT) in moderate and severe house dust mite (HDM) allergic asthmatics. METHODS: Fifty-four adult asthmatics allergic to HDM requiring at least inhaled corticosteroids (ICS) doses equivalent to 500 microg fluticasone propionate daily were randomized to subcutaneous SIT or placebo injections for a period of 3 years. The minimum required ICS dose, 4 week diary of asthma symptom score, use of rescue medication, peak expiratory flow (PEF) measurements and visual analog scale for asthma symptoms were assessed before start of treatment and after 1, 2 and 3 years of treatment. RESULTS: In patients with moderate and severe asthma, the reduction in ICS was statistical significant after 2 years of treatment (P = 0.03) but not after 3 years. The median reductions were 82% and 42% after the third year for active and placebo respectively. In patients with moderate persistent asthma the reduction was statistical significant larger for those treated with SIT compared with placebo after year 2 and year 3. The median reductions after 3 years were 90% for SIT and 42% for placebo (P = 0.04). Despite significant steroid reduction, there was no difference in asthma assessments between the two groups. No serious reactions related to SIT injections were seen. CONCLUSION: This study shows that SIT with a SQ-standardized HDM extract is safe. An ICS sparing effect was evident in patients with moderate persistent asthma.     

Inhaled corticosteroids decrease vascularity of the bronchial mucosa in patients with asthma

BACKGROUND: Increased vascularity in airway mucosa is a distinctive feature of airway remodelling in asthma. While corticosteroids have proved most effective in modifying airway inflammation, the effect of inhaled corticosteroids on increased airway mucosal vascularity in asthmatics has been little studied. OBJECTIVE: We examined the effect of inhaled corticosteroid on airway vascularity in bronchial biopsy specimens taken from asthmatic patients. SUBJECTS AND METHODS: We studied bronchial biopsies from 28 asthmatic patients before and after treatment with inhaled beclomethasone dipropionate (BDP) 800 microg/daily, or placebo, for 6 months in a double-blind manner. Biopsy specimens were evaluated for number of vessels and percentage of area occupied by vessels, using computerized image analysis after staining for type IV collagen in vessel walls. Specimens were also examined for extent of collagen III in the subepithelial basement membrane. In addition, we compared asthmatic specimens with biopsy specimens taken from non-asthmatic control subjects. RESULTS: There was a significant increase in number of vessels (P < 0.01) and percent vascularity (P < 0.001) in the submucosa of asthmatic patients compared with control subjects. After 6 months of treatment, we observed significant improvements in forced expiratory volume in 1 s (FEV1), FEV1% and airway responsiveness (P < 0.05, each) in the BDP treatment group compared with the placebo group. This was accompanied by significant decreases in both vessel number and percent vascularity in the airways of BDP-treated patients (P < 0.05, each). We also observed a significant correlation between change in percent vascularity and change in collagen III thickness in the BDP-treated patients (rs = 0.90, P < 0.001). Furthermore, the change in percent vascularity was inversely correlated with both FEV1 (rs = -0.49, P < 0.05) and airway responsiveness (rs = -0.36, P < 0.05). CONCLUSION: These findings suggest that inhaled corticosteroid treatment of asthma reduced airway wall vascularity during airway remodelling.     

Analysis of induced sputum before and after withdrawal of treatment with inhaled corticosteroids in asthmatic patients

To assess whether sputum eosinophilia predicts the recurrence of asthma symptoms after withdrawal of therapy in moderate stable asthmatics on low-dose inhaled corticosteroids. Randomized, double-blind, placebo-controlled study involving 30 subjects with stable asthma, asymptomatic, with low PEF variability measured over two run-in weeks, on treatment with low-dose inhaled beclomethasone dipropionate (BDP, 250 microgram b.i.d. in the last 3 months). At the end of the run-in, all patients underwent a methacholine challenge test and sputum induction (T1). They then stopped therapy and received either placebo (20 subjects, study group) or BDP at the same dose as in the previous 3 months (10 subjects, control group). They continued to monitor PEF and symptom score for 3 months, or until asthma symptoms recurred (diurnal and nocturnal symptom score >/=2 on two consecutive days). At the end of the study (T2), i.e., either within 5 days from the beginning of asthma symptoms or after 3 months in subjects without recurrence of asthma symptoms, all subjects repeated the methacholine challenge test and sputum induction. In the placebo-treated group, sputum eosinophils at T1 were significantly higher in subjects who subsequently developed recurrence of asthma symptoms (n = 7) after cessation of treatment than in subjects who remained asymptomatic for 3 months (8.2% [0-56.6] vs 0.9% [0-11], P < 0.05). At the time of recurrence of asthma symptoms, sputum eosinophil percentages significantly increased (from 8.2% [0-56.6] to 16.6% [5.8-73.6], P < 0.05). The positive predictive value of sputum eosinophils for the recurrence of asthma symptoms was 71%, while the negative predicting value was 84%. In the BDP-treated control group, none of the subjects experienced recurrence of asthma symptoms, and sputum eosinophil percentages measured at the beginning (T1) and at the end (T2) of the study were similar. Sputum eosinophil percentages may vary over a wide range in asthmatic subjects, although regularly treated and apparently well controlled. However, high sputum eosinophil percentages are related to early recurrence of asthma symptoms after cessation of inhaled corticosteroids.     

Eotaxin in induced sputum of asthmatics: relationship with eosinophils and eosinophil cationic protein in sputum

BACKGROUND: Eosinophilic inflammation is a crucial aspect of allergic diseases such as bronchial asthma. An eosinophil-active chemokine, eotaxin, may play a role in the pathogenesis of the tissue eosinophilia accompanying asthma. METHODS: Induced sputa were obtained from 53 patients with atopic asthma and six healthy subjects, and the concentration of eotaxin in the sputum was measured by ELISA. We investigated whether the sputum content of eotaxin is related to 1) asthma status or corticosteroid therapy, and 2) other sputum indices, including percentage of eosinophils and concentration of eosinophil cationic protein (ECP). RESULTS: The patients with stable or unstable asthma showed significantly higher concentrations of sputum eotaxin than the normal controls. The level of sputum eotaxin demonstrated a positive correlation with the percentage of eosinophils in stable asthmatics not receiving corticosteroid therapy, but not in stable patients treated with corticosteroids, or in unstable patients. Sputum eotaxin demonstrated a positive correlation with ECP in asthmatic patients who were either in a stable state or not receiving steroid therapy. CONCLUSIONS: The elevated level of eotaxin detected in association with increased eosinophils and ECP in the sputum of asthmatics suggests that eotaxin is involved in the pathogenesis of eosinophilic airway inflammation. The relationship of eotaxin to airway eosinophilia may be modified by the stability status of asthma and corticosteroid therapy.     

Increased release of matrix metalloproteinase-9 in the plasma of acute severe asthmatic patients.

BACKGROUND: Matrix metalloproteinases (MMPs) are likely to be relevant mediators of the extracellular matrix (ECM) degradation and airway remodelling. OBJECTIVE: We have compared the levels of MMPs, eotaxin and soluble interleukin 2 receptor (IL-2R) in the plasma of healthy subjects, atopic patients and asthmatic patients. METHODS: The asthmatic patients were separated into two groups, either well controlled on inhaled therapy or acute severe asthma. Patients with acute severe disease had all received systemic corticosteroids from 12 to 48 h before the blood was taken. Blood was recovered in EDTA tubes, incubated with either f MLP, PMA or vehicle for 10 min and centrifuged. MMP-9, TIMP-1, IL-2R and eotaxin levels were measured in the plasma by ELISA. Moreover, the activity of MMPs was also evaluated by zymography. RESULTS: An increased basal level of MMP-9 and IL2-R was observed in acute severe asthma. Following stimulation with f MLP and PMA there was an enhanced production of MMP-9 in the plasma of all groups of patients. However, the MMP-9 level was significantly enhanced in acute severe asthma, compared with the others. No difference was found for the TIMP-1 level between the patients. The eotaxin level in plasma was found to be significantly lower in acute severe asthmatics compared with the others groups. Zymography technique showed a significant increased activity of MMP-9 (92 kDa) but not MMP-2 (66 kDa) in the plasma of patients with acute asthma. CONCLUSION: The increased in MMP-9 production and activity observed in the present study suggests a process of extracellular matrix degradation in acute severe asthmatic patients and proposes MMP-9 as a non-invasive systemic marker of inflammation and airway remodelling in asthma.     

Effects of low dose fluticasone/salmeterol combination on surrogate inflammatory markers in moderate persistent asthma

BACKGROUND: Noninvasive surrogate markers provide valuable information on the asthmatic inflammatory process. We wished to examine the effects of low dose fluticasone/salmeterol combination on different commonly used inflammatory markers in moderate persistent asthma. METHODS: Twenty-five moderate persistent atopic asthmatics were enrolled of whom 20 completed an open label study. Following an initial 4 week steroid washout period in which patients took salmeterol 50 microg dry powder inhaler 1 puff BD, they received the addition of fluticasone as fluticasone 100 microg/salmeterol 50 microg combination dry powder inhaler 1 puff BD for the next 2 weeks. Exhaled nitric oxide, spirometry, methacholine PD20, sputum/blood eosinophils and sputum/serum eosinophil cationic protein (ECP) were measured following the salmeterol only and fluticasone/salmeterol combination treatment periods. RESULTS: Compared to salmeterol alone (i.e. after the steroid washout), the use of fluticasone/salmeterol combination conferred significant improvements (P < 0.05) in all surrogate markers of inflammation apart from serum ECP. Geometric mean fold changes were 4.3-fold/1.3-fold for sputum/blood eosinophils, 2.2-fold/1.2-fold for sputum/serum ECP, 2.3-fold for methacholine PD20 and 1.8-fold for exhaled nitric oxide. CONCLUSIONS: Surrogate markers apart from serum ECP may be used as a guide to evaluate the anti-inflammatory effects of low dose inhaled corticosteroids. Sputum markers tend to be more sensitive than blood when assessing the anti-inflammatory response.     

Attenuated production of intracellular IL-10 and IL-12 in monocytes from patients with severe asthma

Interleukin (IL)-10 and IL-12 production is decreased in peripheral blood mononuclear cells of patients with mild asthma. Using whole blood culture and flow cytometry we examined whether monocyte heterogeneity influenced IL-10 and IL-12 production in subjects with severe asthma. We demonstrated that IL-10 release in LPS-stimulated whole blood culture was decreased in patients with severe persistent asthma compared to those with mild asthma and controls (P = 0.04 and P < 0.001, respectively). In asthmatic patients, the percentage of CD14(+)CD16(+) cells was higher than that from normal subjects (P = 0.04). Severe asthmatics showed significantly less positive staining for IL-10 and IL-12 (P < 0.001 and P = 0.02, respectively) after stimulation in monocytes, compared to mild asthmatics and controls in both CD14(+)CD16(+) and CD14(+)CD16(minus sign) cells. These results suggest that IL-10 synthesis is attenuated in severe persistent asthma compared to mild asthma and that this cannot be explained by the increase in the CD14(+)CD16(+) monocytes in asthma.     

Mild asthma: an expert review on epidemiology, clinical characteristics and treatment recommendations

This review is the synthesis of a working group on mild asthma. Mild asthma includes intermittent and persistent mild asthma according to the Global Initiative for Asthma (GINA) classification, and affects between 50% and 75% of asthmatic patients. Mild asthma is more frequent, more symptomatic, and less well controlled in children than in adults. Cohort studies from childhood to adulthood show that asthma severity usually remains stable over time. Nevertheless, mild asthma can lead to severe exacerbations, with a frequency ranging from 0.12 to 0.77 per patient-year. Severe exacerbations in mild asthma represent 30-40% of asthma exacerbations requiring emergency consultation. In mild asthma, inflammation and structural remodelling are constant, of varying intensity, but nonspecific. Therapy with inhaled corticosteroids (ICS) decreases bronchial inflammation, but has only a slight effect on structural remodelling, and, when stopped, inflammation immediately recurs. Permanent low-dose ICS therapy is the reference treatment for persistent mild asthma. Effectiveness is to be reassessed at 3 months, and if it is insufficient the patient is no longer considered mildly asthmatic, and treatment has to be stepped up. As mild asthma is the most frequent form of the disease, diagnosis and management require physicians' particular attention.     

Leukotriene receptor antagonist, montelukast, can reduce the need for inhaled steroid while maintaining the clinical stability of asthmatic patients

BACKGROUND: Oral leukotriene receptor antagonists have been shown to have efficacy in chronic asthma. OBJECTIVE: To determine whether the addition of montelukast could lead to a reduction in inhaled corticosteroid dose without a significant decrease in peak expiratory flow rate (PEFR). METHODS: After a 4-week run-in period, 191 moderate-to-severe asthmatic patients whose asthma had been well controlled with daily inhaled corticosteroid therapy (beclometasone dipropionate 800 to 1600 micro g/day), were randomly assigned to one of two treatments - placebo (n = 98) or montelukast 10 mg once daily (n = 93) - for a 24-week, multicentre, double-blind, treatment period. At the beginning of the active treatment period, the daily dose of inhaled corticosteroid was halved in all of the patients. In addition, the inhaled corticosteroid dose was subsequently titrated every 8 weeks, based on PEFR, asthma symptoms and beta-agonist use. RESULTS: After 8 weeks of a 50% reduction in inhaled corticosteroid use, morning PEFR increased by 5.3 +/- 32.3 L/min from baseline in patients receiving montelukast and significantly decreased by 6.9 +/- 29.0 L/min in those receiving placebo (P = 0.035). In addition, evening PEFR significantly decreased by 9.8 +/- 28.5 L/min (P = 0.003) in the placebo group, but was maintained in the montelukast group. In spite of a subsequent 50% reduction in the inhaled corticosteroid dose every 8 weeks, morning and evening PEFRs were maintained over the 24-week treatment period in the montelukast group; PEFR significantly decreased in the placebo group. There was a significant difference between the two groups with regard to morning PEFR, therapy score and asthmatic score at weeks 8, 16 and 24, as well as evening PEFR at week 8. However, the symptom scores were not significantly different between the two groups or within each group. CONCLUSION: These data suggest that montelukast reduces the need for inhaled corticosteroids while maintaining asthma control over a 24-week period. Therefore, montelukast may be useful for long-term treatment in patients with asthma who require high doses of inhaled corticosteroids.