Background -Current guidelines on the management of asthma advocate the use of anti-inflammatory treatment in all but mild disease. They define disease control in terms of clinical criteria such as lung function and symptoms. However, the relationship between the clinical control of the disease and inflammation of the airways is not clear. A cross sectional study was therefore undertaken to investigate the relationship between airways inflammation and measures of clinical control and bronchial hyperresponsiveness in asthmatic patients treated with inhaled steroids. Methods -Twenty six atopic adults (19-45 years) with mild to moderate asthma (baseline forced expiratory volume in one second (FEVy) . 50% predicted, concentration of histamine causing a 20% fall in FEV1 (PC20) 0-02-7-6 mglml) on regular treatment with inhaled steroids entered the study. Diary card recordings during the two weeks before a methacholine challenge test and bronchoscopic examination were used to determine peak flow variability, symptom scores, and use of P2 agonists. Biopsy specimens were taken by fibreoptic bronchoscopy from the carina of the right lower and middle lobes, and from the main carina. Immunohistochemical staining was performed on cryostat sections with monoclonal antibodies against: eosinophil cationic protein (EG1, EG2), mast cell tryptase (AA1), CD45, CD22, CD3, CD4, CD8, CD25, and CD45RO. The number of positively stained cells in the lamina propria was counted twice by using an interactive display system. Results -There were no differences in cell numbers between the three sites from which biopsy specimens were taken. The PC20 for methacholine was inversely related to the average number of total leucocytes, EG1 +, and EG2 + cells, mast cells, CD8 +, and CD45RO + cells in the lamina propria. These relationships were similar for each of the biopsy sites. Symptom scores, P2 agonist usage, FEV1, and peak flow variability were not related to any of the cell counts.Conclusions -Infiltration ofinflammatory cells in the lamina propria of the airways seems to persist in asthmatic outpatients despite regular treatment with inhaled steroids. The number ofinfiltrating leucocytes such as mast cells, (activated) eosinophils, CD8 +, and CD45RO + cells in bronchial biopsy specimens from these patients appears to be reflected by airway hyperresponsiveness to methacholine, but not by symptoms or lung function. These findings may have implications for the adjustment of anti-inflammatory treatment of patients with asthma. (Thorax 1996;51:496-502) Keywords: atopic asthma, bronchial responsiveness, inflammatory infiltrate.hyperAsthma is a chronic inflammatory disorder of the airways with a characteristic infiltrate of mast cells, lymphocytes, and eosinophils in the bronchial epithelium and lamina propria.'2 The symptoms ofwheezing, chest tightness, difficult breathing, and coughing develop after exposure to bronchoconstrictor stimuli and are associated with variable airways obstruction3 which can be provoked in the laboratory, ther...

The outcome of asthma, as determined by the annual decline in FEV1, can be predicted by the bronchial CD8+ cell infiltrate. This suggests that the inflammatory phenotype in asthma has prognostic relevance, which may require phenotype-specific therapeutic strategies.

The response to inhaled allergen in asthma is diminished by anti-IgE, which in bronchial mucosa is paralleled by a reduction in eosinophils and a decline in IgE-bearing cells postallergen without changing PC(20) methacholine. This suggests that the benefits of anti-IgE in asthma may be explained by a decrease in eosinophilic inflammation and IgE-bearing cells.

Asthma is a chronic inflammatory disease that persists even during adequate therapy and asymptomatic episodes. We questioned whether "silent" chronic allergen exposure can induce and maintain airway inflammation and whether this still occurs during regular treatment with inhaled steroids. Twenty-six patients with house dust mite allergy and mild asthma (dual responders) participated in a parallel, double-blind study. All patients inhaled a low-dose of allergen on 10 subsequent working days (Days 1-5, 8-12). They were treated with 400 micro g budesonide once daily (n = 13) or placebo (n = 13) from Days -3 to 19. At baseline (Day -6) and on Days 5, 12, and 19 we measured the provocative concentration of methacholine causing a 20% fall in FEV(1) (PC(20)), and percent eosinophils, interleukin (IL)-5/interferon-gamma messenger RNA ratio (in sputum cells by real-time reverse transcription-polymerase chain reaction [RT-PCR]), and eosinophilic cationic protein (ECP) in induced sputum. Symptoms, peak expiratory flow (PEF), FEV(1), and exhaled nitric oxide (NO) were recorded repeatedly during the study. In the placebo group, repeated low-dose allergen exposure resulted in a significant increase in sputum eosinophils (p = 0.043), ECP (p = 0.011), IL-5/IFN-gamma messenger RNA ratio (p = 0.04), and in exhaled NO (p = 0.001), without worsening of symptoms, PEF, or baseline FEV(1) (p > 0.07). In the budesonide group, the changes in PC(20), sputum ECP, and exhaled NO were significantly different as compared with the placebo group (p < 0.03). We conclude that repeated low-dose allergen exposure in asthma can lead to airway inflammation without worsening of symptoms, which can be prevented by inhaled steroid treatment. This suggests that antiinflammatory therapy is beneficial during allergen exposure, even during asymptomatic episodes.

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.