The effect of aerosol distribution on airway responsiveness to inhaled methacholine in patients with asthma.

It has been demonstrated that airway deposition of inhaled aerosols is more heterogeneous in patients with asthma than in normal subjects. Nevertheless, the influence of abnormal airway deposition on responses to bronchoactive aerosols is poorly understood. We altered bronchopulmonary deposition heterogeneity of methacholine aerosol in nine asymptomatic patients with asthma by controlling inspiratory flow at high (approximately 60 L/min) versus low (approximately 12 L/min) rates on 2 study days and determined the effect on the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) (often used as a measure of airway responsiveness). Deposition uniformity was quantified from gamma-camera scans of the lungs in terms of the distribution of a technetium-labeled aerosol that was inhaled rapidly or slowly before the inhalation of methacholine. Increased deposition in an inner (large, central airways) versus an outer (peripheral airways and alveoli) zone of the right lung (inner/outer ratio, greater than 1) and higher values of skew (an index of deposition asymmetry) and kurtosis (an index of deposition range) indicated enhanced heterogeneity of deposition. Mean (+/- SD) inner/outer ratio was significantly higher during rapid inspiration compared to slow inspiration with 2.91 +/- 0.51 and 1.84 +/- 0.30, respectively (p less than 0.01). Mean skew and kurtosis were also significantly higher after rapid inspiration, with 1.12 +/- 0.35 and 3.86 +/- 1.25, respectively, compared to 0.74 +/- 0.36 and 2.64 +/- 0.77 after slow inhalation (p less than 0.01). Geometric mean PD20 methacholine was significantly reduced when the aerosol was inhaled rapidly, with 5.9 cumulative methacholine units compared to 15.7 units after slow inhalation (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Combined mediator blockade or topical steroid for treating the unified allergic airway

BACKGROUND: Asthma and allergic rhinitis are manifestations of a single unified allergic airway, for which the best treatment is uncertain. OBJECTIVE: To compare the anti-inflammatory efficacy in the unified allergic airway of combined oral mediator antagonism and combined topical steroid. METHODS: Subjects with asthma and perennial allergic rhinitis entered a randomized double blind crossover study comparing montelukast 10 mg and cetirizine 10 mg to extra-fine inhaled beclomethasone 400 mcg/day and intranasal beclomethasone 200 mcg/day, each taken once daily for 2 months, after 2-week placebo washouts. Measurements were made after each washout and randomized treatment, comprising: methacholine PC20, exhaled and nasal nitric oxide, blood eosinophils and eosinophilic cationic protein, symptoms, lung and nasal function tests. RESULTS: Seventeen patients completed per protocol. For PC20 and exhaled nitric oxide, only combined topical steroid produced improvements (P < 0.005) from placebo baseline. Combined steroid was superior by a 0.93 (95% CI 0.14-0.93, P < 0.05) doubling dilution difference for PC20 and a 0.99 (95% CI 0.9-15.1, P < 0.01) doubling difference for exhaled nitric oxide. Both treatments attenuated eosinophils and eosinophilic cationic protein, and reduced nasal symptoms (P < 0.05). Only steroid improved nasal nitric oxide (P=0.05) and asthma symptoms (P < 0.05). Neither treatment affected lung or nasal function tests. CONCLUSION: Combined topical steroid and combined mediator antagonism both attenuated systemic inflammation in the unified allergic airway, but only the former reduced bronchial and nasal inflammatory markers. The relevance of this to exacerbations and airway remodelling needs to be defined.     

Bronchodilation and bronchoconstriction: predictors of future lung function in childhood asthma

BACKGROUND: Persistently low levels of lung function are associated with subsequent symptoms in patients with asthma as children. OBJECTIVES: We hypothesized that objective measures of baseline pulmonary function would be independently associated with future lung function in the Childhood Asthma Management Program and that these associations might vary with treatment. METHODS: We evaluated the association of FEV1, airway responsiveness, and bronchodilator response at randomization as predictors of longitudinal growth in FEV1 at the 48-month follow-up visit in the 1041 Childhood Asthma Management Program participants. RESULTS: Baseline levels of airway responsiveness and bronchodilator response were significantly associated with baseline level of lung function. In multivariate models, higher bronchodilator response (beta = 0.22; P < .0001), log PC20 (beta = 1.82; P < .0001), and FEV1 (beta = 0.58; P < .0001) at randomization were each associated with higher levels of prebronchodilator FEV1, as a percent of predicted, after 4 years. Similar associations were noted for prebronchodilator forced vital capacity and FEV1/forced vital capacity ratio. Baseline bronchodilator response was a particularly powerful predictor of lung function improvements while on inhaled corticosteroids, whereas airway responsiveness was a better predictor in subjects not randomized to any controller medications. CONCLUSION: We conclude that baseline bronchodilator response, airway responsiveness, and level of FEV1 are independent predictors of subsequent level of FEV1 in childhood asthma and may have treatment-specific prognostic significance for persistence of symptoms into early adulthood. CLINICAL IMPLICATIONS: In asthma, bronchodilator and bronchoconstrictor responses are independent predictors of future lung function and should not be used interchangeably; bronchodilator response may indicate good response to inhaled corticosteroids.     

The relationship between airway hyper‐responsiveness, markers of inflammation and lung function depends on the duration of the asthmatic disease

BACKGROUND: The combination of airway hyper-responsiveness, eosinophilic airway inflammation, and lung function impairment is considered as a hallmark of bronchial asthma. Since airway function might change with time in chronic asthma, the association between parameters which are characteristic of asthma could be different in subjects with different durations of the disease. OBJECTIVE: We assessed whether in patients with asthma the relationship between airway hyperresponsiveness, non-invasive markers of airway inflammation, and baseline lung function depended on the duration of the disease. METHODS: Sixty-six non-smoking patients with mild to moderate allergic asthma without corticosteroids were assigned to two groups, according to a duration of the disease (time interval since doctor's diagnosis) of either < or = 16 years (median 8 years; mean FEV1, 92.6% pred.; n = 34) or > 16 year (median 25 years; mean FEV1, 87.9% pred.; n = 32). RESULTS: Groups did not differ statistically in PC20FEV1 of methacholine, sputum composition, levels of exhaled nitric oxide (NO), lung function parameters, or history of treatment. There were significant correlations between PC20FEV1, eosinophils and NO in patients with a duration of the disease < or = 16 year, but no relation to lung function. In contrast, patients with a duration > 16 year showed a correlation between PC20FEV1 of methacholine and lung function but not eosinophils or NO. In both groups, eosinophils and NO were associated with each other. These results were corroborated by the statistical procedure of factor analysis that revealed 'inflammation' and 'lung function' as major entities and found 'responsiveness' to be associated with only one of them in each group. CONCLUSION: Our data demonstrate that with a shorter duration of the asthmatic disease airway hyper-responsiveness is associated with airway inflammation, whereas with a longer duration it is associated with impaired lung function, suggesting that in chronic asthma ongoing alterations become the primary determinant of functional characteristics.     

Involvement of distal airways in a chronic model of experimental asthma

BACKGROUND: Bronchial asthma is characterized by chronic airway inflammation and airway remodelling which occurs in both proximal and distal airways. These changes are associated with development of airway hyper-responsiveness and airflow limitation. OBJECTIVE: This study was aimed to analyse whether chronic inhalative allergen challenges in mice lead to morphological and physiological changes comparable with this phenotype. METHODS: For this purpose, BALB/c mice were systemically sensitized to ovalbumin (OVA) followed by aerosol allergen challenges on 2 consecutive days per week for 12 weeks. RESULTS: In chronically challenged mice, tissue inflammation in proximal as well as distal airways was observed with a predominance of lymphocytes within the cellular infiltrate. In contrast, inflammation in the airway lumen decreased over time. These changes were associated by a shift in bronchoalveolar lavage-cytokine levels from IL-4, IL-5 and TNF-alpha production (during the acute phase) towards markedly increased levels of TGF-beta during the chronic phase. Goblet cell hyperplasia and subepithelial fibrosis occurred throughout the airway tree. In terms of lung function, chronically challenged mice developed persistent bronchial hyper-responsiveness and progressive airflow limitation. Six weeks after OVA aerosol discontinuation, airway inflammation still persisted although lung function was normalized. CONCLUSION: These data indicate that our model of chronic aerosol allergen challenges leads to a phenotype of experimental asthma with participation of distal airways and persistence of inflammation thereby resembling many morphological and physiological aspects of human bronchial asthma.     

Effect of therapy on bronchial hyperresponsiveness in the long-term management of asthma

The aim of this study was to determine if prophylactic therapy leads to a reduction in the severity of bronchial hyperresponsiveness (BHR) in subjects with severe asthma. Measurements of bronchial responsiveness to histamine were made in two groups of subjects for periods up to 2 years. Thirteen subjects in the study group took regular medication and used a home monitor of airway function to determine the medication requirements needed to maintain optimal airway function. A control group of eleven subjects was managed with the same drugs but without daily monitoring and without any attempt to keep daily lung function at optimal levels. Subjects in the study group had a 10- to 100-fold decrease in the severity of BHR, which was independent of the improvement in baseline lung function. All but one subject in the study group became symptom free and six were able to maintain the improvement in BHR and symptoms on reduced medication. There was no change in the severity of BHR or in the baseline lung function in the control group. It is concluded that it is possible to reduce the severity of BHR in subjects with severe asthma by the use of pharmacological agents. This reduction in severity appears to require the long-term use of medications, including aerosol corticosteroids, with daily home monitoring to allow adjustment of the amount of treatment required.     

Ovalbumin-sensitized mice are good models for airway hyperresponsiveness but not acute physiological responses to allergen inhalation

Background Asthma is a chronic inflammatory disease that is characterized clinically by airway hyperresponsiveness (AHR) to bronchoconstricting agents. The physiological response of the asthmatic lung to inhaled allergen is often characterized by two distinct phases: an early‐phase response (EPR) within the first hour following exposure that subsides and a late‐phase response (LPR) that is more prolonged and may occur several hours later. Mouse models of asthma have become increasingly popular and should be designed to exhibit an EPR, LPR and AHR. Objective To determine whether a common model of asthma is capable of demonstrating an EPR, LPR and AHR. Methods BALB/c mice were sensitized to ovalbumin (OVA) and challenged with one or three OVA aerosols. Changes in lung mechanics in response to allergen inhalation were assessed using a modification of the low‐frequency forced oscillation technique (LFOT). In order to assess AHR, changes in lung mechanics in response to aerosolized methacholine were assessed using LFOT. Inflammatory cell infiltration into the lung was measured via bronchoalveolar lavage (BAL). ELISAs were used to measure inflammatory cytokines in the BAL and levels of IgE in the serum. Results An EPR was only detectable after three OVA aerosols in approximately half of the mice studied. There was no evidence of an LPR despite a clear increase in cellular infiltration 6 h post‐allergen challenge. AHR was present after a single OVA aerosol but not after three OVA aerosols. Conclusions The lack of an LPR, limited EPR and the absence of a link between the LPR and AHR highlight the limitations of this mouse model as a complete model of the lung dysfunction associated with asthma.     

Risk factors associated with irreversible airflow limitation in asthma

PURPOSE OF REVIEW: Irreversible airflow limitation develops in some patients with asthma and is related to poorer prognosis. This paper reviews recent literature on natural course, risk factors, and potential mechanisms of persistent airflow limitation in asthma. RECENT FINDINGS: The natural course of persistent airflow limitation in asthma is poorly known, but reduced lung function at disease onset and an increased rate of decline during adult life contribute to its development. Risk factors for progressive irreversible airway obstruction in asthma include adult onset, frequent exacerbations, smoking, occupational exposure, ongoing eosinophilic airway inflammation and airway hyperresponsiveness. Polymorphisms of the ADAM33 gene predict excess decline in lung function, in asthma as well as at population level. It is still not clear how different components of airway remodeling affect lung function in asthma. Airway epithelium and airway smooth muscle seem to be highly important, but the interrelationship between persistent airflow limitation, airway inflammation, remodeling and airway hyperresponsiveness has not been clearly defined. SUMMARY: Whereas several factors have been implicated as being important in the development of fixed airway obstruction in asthma, we are just beginning to explore the different components of airway remodeling and their relevance, deleterious or beneficial, to clinical outcome.     

Gas mixing efficiency from birth to adulthood measured by multiple-breath washout

Efficient mixing of inspired gas with the resident gas of the lung is an essential requirement of effective respiration. This review focuses on one method for quantifying ventilation inhomogeneity: the multiple-breath inert gas washout (MBW). MBW has been employed as a research tool in adults and school age children for more than 50 years. Modifications allowing data collection in infants and preschoolers have been described recently. Indices of overall ventilation inhomogeneity, such as the lung clearance index and moment ratios, are raised in many infants with lung disease of prematurity, and in young children with cystic fibrosis. These indices may be more sensitive than other lung function measures for the early detection of airway disease. We describe, for the first time, a development of the MBW analysis that allows calculation of acinar and conductive zone inhomogeneity indices in spontaneously breathing children. Although methodological and analytical issues remain, the future clinical and research applications of MBW justify accelerated research in this field.     

Experimental rhinovirus challenges in adults with mild asthma: response to infection in relation to IgE

BACKGROUND: Although most children and young adults with asthma are atopic, exacerbations of asthma are frequently associated with viral respiratory tract infections, especially those caused by rhinovirus (HRV). OBJECTIVE: Young atopic adults with mild asthma were evaluated before and during an experimental HRV infection to test the hypothesis that airway inflammation before virus inoculation may be a risk factor for an adverse response to HRV. METHODS: Experimental HRV infections were evaluated in 16 allergic volunteers with mild asthma and 9 nonatopic control patients (age, 18 to 30 years). Before virus inoculation, each participant was screened with tests for lung function, prick skin tests for sensitization to common aeroallergens, measurements of total serum IgE, and serum neutralizing antibody to rhinovirus-16 (the serotype used for inoculation). The response to infection was monitored for 21 days by using symptom diary cards, tests for lung function, and markers of airway inflammation in nasal washes, blood, and expired air. RESULTS: During the infection, asthmatic patients had cumulative upper and lower respiratory tract symptom scores that were significantly greater over the course of 21 days than scores from the control patients. At baseline, the asthmatic patients also had increased sensitivity to methacholine and significantly lower values for FEV(1) (percent predicted) than the control patients (geometric mean and intraquartile values: 87% [79% to 91%] for the asthmatic patients and 101% [90% to 104%] for the control patients, P <.03). Among the patients with mild asthma, 6 had levels of total serum IgE that were substantially elevated (range, 371 to 820 IU/mL) compared with 10 who had lower levels (range, 29 to 124 IU/mL). Those with high levels of IgE had significantly greater lower respiratory tract symptom scores during the initial 4 days of the infection than the low IgE group. They also had higher total blood eosinophil counts at baseline, increased eosinophil cationic protein in their nasal washes (>200 ng/mL), and augmented levels of expired nitric oxide at baseline and during peak cold symptoms. In contrast, levels of soluble intracellular adhesion molecule-1 in nasal wash supernatants from the asthmatic patients with high IgE were diminished, both at baseline and during the infection. CONCLUSIONS: The reduced lung function and increased markers of inflammation observed before virus inoculation in the asthmatic patients who had high levels of total serum IgE may be risk factors for an adverse response to infections with HRV.     

Sequential development of airway hyperresponsiveness and acute airway obstruction in a mouse model of allergic inflammation

BACKGROUND: Mouse models have been established mirroring key features of human bronchial asthma including airway hyperresponsiveness (AHR). Acute airway obstruction in response to an allergen challenge, however, remains to be demonstrated in these models. OBJECTIVE: A mouse model of allergic lung inflammation was employed to analyze the development of specific (allergen-induced) and nonspecific (methacholine-induced) airway obstruction. METHODS: Mice were sensitized to ovalbumin (OVA) and challenged with OVA aerosol twice each week during four weeks. Changes in lung functions were determined by noninvasive head-out body plethysmography. The development of acute airway obstruction after OVA challenge and AHR after methacholine aerosol application were assessed by a decrease in the mid-expiratory flow rate (EF(50)). Results: Two airway challenges were sufficient to induce AHR (5.7 vs. 15 mg/ml methacholine). Further OVA challenges reduced the baseline EF(50) from 1.85 to 1.20 ml/s (4th week) and induced acute airway obstruction. The OVA-induced obstruction was maximal in the 4th week (EF(50) = 0.91 ml/s). CONCLUSION: The development of acute airway obstruction in allergen-sensitized mice was demonstrated by means of head-out body plethysmography. In our model, AHR was observed before the development of airway obstruction.     

支气管哮喘患者血清嗜酸细胞阳离子蛋白的变化

探讨检测血清嗜酸细胞阳离子蛋白在支气管哮喘的诊断１病情监测及疗效判断中的价值。方法采用荧光酶免疫法测定了发作期和缓解哮喘患者各２０例,慢性阻塞性肺疾病患者１６例和正常人２０例的血清ＥＣＰ,同时进行了肺功能测定,并对发作期哮喘患者在给予吸入皮质激素治疗３ｍｏ后复测其ＥＣＰ及肺。     

Comparison of salbutamol Rotahaler with conventional pressurized aerosol

Salbutamol in a powder aerosol from the Rotahaler insufflator was compared, with equal doses of the conventional pressurized aerosol by dose-response curves and in a 1 month open trial, in the treatment of asthma patients with good inhalation technique. Results were not significantly different in either study. A further group of asthma patients, who were known to be incapable of using pressurized aerosols effectively, were shown to benefit from treatment with the Rotahaler. This device should increase the value of the sympathomimetic drugs to the minority of asthma patients who cannot use conventional aerosols correctly.     

A randomized, double-blind comparison of beclomethasone dipropionate extrafine aerosol and fluticasone propionate.

BACKGROUND: Inhaled corticosteroids provide first-line treatment for asthma. An advance to improve potency was to produce new molecules with increased glucocorticoid receptor affinity (eg, fluticasone propionate [FP]). An alternative is to deliver more medication to both the large and small airway inflammation of asthma by using an extrafine aerosol (eg, beclomethasone dipropionate extrafine aerosol [BDP-extrafinel). OBJECTIVE: To demonstrate clinical equivalence of BDP-extrafine (400 microg daily) and FP (400 microg daily) in symptomatic asthmatic patients over the course of 6 weeks. METHODS: This was a double-blind, double-dummy, parallel-group, multicenter, 6-week study in adults with asthma taking conventional FP 100 to 250 microg daily or equivalent, and displaying signs/symptoms of active disease requiring additional therapy. RESULTS: Eighty-eight patients were randomized to BDP-extrafine (and FP-placebo) and 84 to FP (and BDP-placebo). There were no significant differences between treatments with respect to symptom control, as evidenced by mean change from baseline in percentage days without asthma symptoms/nights without sleep disturbance observed at weeks 1 to 2, 3 to 4, or 5 to 6. Mean changes from baseline in AM PEFR at weeks 5 to 6 for BDP-extrafine (19.0) and FP (30.5) were equivalent (P = 0.022 for equivalence). There were significant (P < 0.001) within-treatment-group differences in mean change from baseline in AM PEFR at weeks 1 to 2 for both treatments. There was no difference in the incidence of patients reporting at least one adverse event during the study (BDP-extrafine 41%; FP 37%). Mean percentage change from baseline for AM plasma cortisol at week 6 was + 17.7% for BDP-extrafine and +4.2% for FP (P = 0.066 for difference). CONCLUSIONS: BDP-extrafine and FP at doses of 400 microg daily provided equivalent asthma control in patients with symptomatic asthma and exhibited similar safety profiles.     

Breathing Resistance and Ultrafine Particle Deposition in Nasal–Laryngeal Airways of a Newborn, an Infant, a Child, and an Adult

As a human grows from birth to adulthood, both airway anatomy and breathing conditions vary, altering the deposition rate and pattern of inhaled aerosols. However, deposition studies have typically focused on adult subjects, results of which may not be readily extrapolated to children. This study numerically evaluated the age-related effects on the airflow and aerosol dynamics in image-based nose?Cthroat models of a 10-day-old newborn, a 7-month-old infant, a 5-year-old child, and a 53-year-old adult. Differences in airway physiology, breathing resistance, and aerosol filtering efficiency among the four models were quantified and compared. A high-fidelity fluid-particle transport model was employed to simulate the multi-regime airflows and particle transport within the nasal?Claryngeal airways. Ultrafine particles were evaluated under breathing conditions ranging from sedentary to heavy activities. Results of this study indicate that the nasal?Claryngeal airways at different ages, albeit differ significantly in morphology and dimension, do not significantly affect the total deposition fractions or maximum local deposition enhancement for ultrafine aerosols. Further, the deposition partitioning in the sub-regions of interest is different among the four models. Results of this study corroborate the use of the in vivo-based diffusion parameter (D ^0.5 Q ^?0.28) over the replica-based parameter in correlating nasal?Claryngeal depositions of ultrafine aerosols. Improved correlations have been developed for the four age groups by implementing this in vivo-based diffusion parameter as well as the Cunningham correction factor.     

Switching from conventional to extrafine aerosol beclomethasone dipropionate therapy in children: a 6-month,open- label,randomized trial

BACKGROUND: In adults with asthma, hydrofluoralkane-134a beclomethasone dipropionate (HFA-BDP) extrafine aerosol provides equivalent asthma control at half the daily dose of conventional chlorofluorocarbon (CFC)-BDP. OBJECTIVE: We sought to compare the efficacy and tolerability of switching from CFC-BDP to HFA-BDP at half the daily dose in children with stable asthma. METHODS: This 6-month, open-label, randomized, multicenter study enrolled 520 children aged 5 to 11 years with well-controlled asthma receiving inhaled CFC-BDP or budesonide 200 to 800 microg/d x. (Four hundred fifty-two patients were using doses within the recommended range of 200-400 microg and were analyzed separately.) During a 4-week run-in period, patients used CFC-BDP plus a spacer (CFC-BDP+S) at approximately the same dose as they were using before study entry. Patients were then randomized in a 1:3 ratio to continue on CFC-BDP+S or switch to HFA-BDP Autohaler at half the daily dose. RESULTS: The change from baseline in morning peak expiratory flow was significantly greater in patients receiving 100-200 microg of HFA-BDP compared with those receiving 200-400 microg of CFC-BDP+S at weeks 7 to 8 (8.5 and 0.4 L/min, respectively; P =.014), with continuing improvement in both groups over 6 months (12.2 and 12.4 L/min, respectively, at month 6). There were no significant differences between treatments in mean change from baseline in FEV(1), percentage of days or nights without asthma symptoms, and daily beta-agonist use over the 6-month treatment period. The proportion of patients who had one or more asthma exacerbations, the incidence of adverse events, and the percentage change from baseline in 24-hour urinary free cortisol levels were similar in the 2 treatment groups. CONCLUSIONS: This study confirms that asthma control can be well maintained in children when switching from CFC-BDP+S to an HFA-BDP Autohaler at doses as low as 100 to 200 microg/d.     

Shifts in Lung Lymphocyte Profiles Correlate with the Sequential Development of Acute Allergic and Chronic Tolerant Stages in a Murine Asthma Model

T lymphocytes have a central regulatory role in the pathogenesis of asthma. We delineated the participation of lymphocytes in the acute allergic and chronic tolerant stages of a murine model of asthma by characterizing the various subsets of lymphocytes in bronchoalveolar lavage and lung tissue associated with these responses. Acute (10-day) aerosol challenge of immunized C57BL/6J mice with ovalbumin resulted in airway eosinophilia, histological evidence of peribronchial and perivascular airway inflammation, clusters of B cells and TCRgammadelta cells in lung tissue, increased serum IgE levels, and airway hyperresponsiveness to methacholine. In mice subjected to chronic (6-week) aerosol challenge with ovalbumin, airway inflammation and serum IgE levels were significantly attenuated and airway hyperresponsiveness was absent. The marked increases in lung B and T cell populations seen in the acute stage were also significantly reduced in the chronic stage of this model. Thus, acute ovalbumin challenge resulted in airway sensitization characteristic of asthma, whereas chronic ovalbumin challenge elicited a suppressed or tolerant state. The transition from antigenic sensitization to tolerance was accompanied by shifts in lymphocyte profiles in the lung and bronchoalveolar lavage fluid.     

Clinical implications of airway inflammation in mild intermittent asthma.

OBJECTIVE: To determine whether inhaled corticosteroids should be prescribed to patients with milder forms of asthma and whether markers of airway inflammation should be considered when making therapy decisions. DATA SOURCES: A PubMed search was performed of the English-language literature published in the preceding 10 years (January 1, 1993, through December 31, 2003) concerning epidemiology, pathophysiology, therapy, and prognosis of mild intermittent asthma, with asthma, mild, and intermittent as indexing terms. STUDY SELECTION: All relevant studies including author's expert opinions were selected. RESULTS: Several studies have addressed the question of a possible benefit of maintenance therapy (ie, inhaled steroids) in patients with mild intermittent asthma. Although a diminishing effect on airway inflammation has been widely demonstrated, even in patients with mild disease, the impact of inhaled steroids on the long-term prognosis is much less clear. For patients with mild disease who are long-term inhaled steroid users, alternative therapy strategies, including low-dose inhaled steroids and leukotriene receptor antagonists, have been advocated. CONCLUSIONS: Mild intermittent asthma is a disease characterized not only by infrequent symptoms and normal lung function but also by chronic airway inflammation, possibly resulting in irreversible airflow limitation if left unattended. Therefore, maintenance therapy, such as (low-dose) inhaled steroids or leukotriene receptor antagonists, should be considered in patients with mild disease. Future studies should give more insight into the impact of prolonged anti-inflammatory therapy on the long-term prognosis of mild intermittent asthma patients. Whether results from these studies will justify a more aggressive treatment for these patients remains to be answered.     

A double-blind, placebo-controlled comparison of sodium cromoglycate and ketotifen in the treatment of childhood asthma

We compared three treatments: sodium cromoglycate 5 mg aerosol and placebo syrup (39 patients), placebo aerosol and ketotifen syrup (39 patients), and placebo aerosol and syrup (36 patients). The patients (mean age 11.7 years) had mostly allergic, moderately severe asthma. Treatments were added to current therapy (mostly bronchodilators only) for 3 months. Aerosols were taken four times daily and syrups twice daily. The following results were significant at a level of 5%. At the final clinic visit, the changes from baseline in lung function favored sodium cromoglycate over the other treatments. During month 3, sodium cromoglycate was superior to ketotifen for night symptoms, morning tightness, daytime symptoms, and cough. Bronchodilator use decreased more with sodium cromoglycate than ketotifen. Patients' and clinicians' overall opinions of treatment effectiveness favored sodium cromoglycate over ketotifen and placebo. In these patients, sodium cromoglycate was both effective and superior to ketotifen.     

Bronchial matrix and inflammation respond to inhaled steroids despite ongoing allergen exposure in asthma

BACKGROUND: Inflammatory and structural changes of the airway mucosa are chronic features of asthma. The mechanisms underlying these changes and their modulation by steroid prophylaxis have not been clarified. OBJECTIVE: We postulated that asymptomatic ongoing allergen exposure could drive airway inflammation as well as changes in the extracellular matrix (ECM), and that inhaled steroids could prevent this. METHODS: Therefore, we exposed patients with mild asthma to 2 weeks of repeated low-dose allergen, with concomitant inhaled steroid or placebo treatment. Bronchial biopsies, which were taken before and after this exposure, were stained and digitally analysed. The ECM proteins in asthmatics were also compared with a normal control group. RESULTS: Low-dose allergen exposure alone resulted in a significant increase of bronchial epithelial macrophages. Despite ongoing allergen exposure, inhaled steroids reduced the numbers of mucosal eosinophils, neutrophils and T lymphocytes. At baseline, the mean density of the proteoglycans (PGS) biglycan and decorin were, respectively, higher and lower in the bronchial mucosa of asthmatics as compared with normal controls. Steroid treatment, during allergen exposure, increased the mean density of the PGS biglycan and versican. CONCLUSION: We conclude that chronic allergen exposure induces inflammatory changes in the bronchial mucosa. Despite ongoing allergen exposure, steroid treatment decreases mucosal inflammatory cells while altering PG density. The latter observation highlights the need to examine steroid-induced changes closely in the airway structure in patients with asthma.