Relationship between the inflammatory infiltrate in bronchial biopsy specimens and clinical severity of asthma in patients treated with inhaled steroids.

J. K. Sont, J. Han, J. M. van Krieken, C. E. Evertse, R. Hooijer, L. N. Willems, P. J. Sterk

Department of Pulmonology, Leiden University Hospital, Netherlands.

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 (FEV1) > or = 50% predicted, concentration of histamine causing a 20% fall in FEV1 (PC20) 0.02-7.6 mg/ml) 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 beta 2 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, beta 2 agonist usage, FEV1, and peak flow variability were not related to any of the cell counts. CONCLUSIONS: Infiltration of inflammatory cells in the lamina propria of the airways seems to persist in asthmatic outpatients despite regular treatment with inhaled steroids. The number of infiltrating 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.

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• van Rensen, E. L J, Straathof, K. C M, Veselic-Charvat, M. A, Zwinderman, A. H, Bel, E. H, Sterk, P. J (1999). Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils, and exhaled nitric oxide levels in patients with asthma. Thorax 54: 403-408 [Abstract] [Full Text]  
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• Jatakanon, A., Kharitonov, S., Lim, S., Barnes, P. J (1999). Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma. Thorax 54: 108-114 [Abstract] [Full Text]  
• LIM, S., JATAKANON, A., JOHN, M., GILBEY, T., O'CONNOR, B. J., CHUNG, K. F., BARNES, P. J. (1999). Effect of Inhaled Budesonide on Lung Function and Airway Inflammation . Assessment by Various Inflammatory Markers in Mild Asthma. Am. J. Respir. Crit. Care Med. 159: 22-30 [Abstract] [Full Text]  
• Stirling, R G, Kharitonov, S A, Campbell, D, Robinson, D S, Durham, S R, Chung, K F, Barnes, P J (1998). Increase in exhaled nitric oxide levels in patients with difficult asthma and correlation with symptoms and disease severity despite treatment with oral and inhaled corticosteroids. Thorax 53: 1030-1034 [Abstract] [Full Text]  
• POSTMA, D. S., KERSTJENS, H. A. M. (1998). Characteristics of Airway Hyperresponsiveness in Asthma and Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 158: S187-S192 [Abstract] [Full Text]  
• Faul, J. L, Leonard, C. T, Burke, C. M, Tormey, V. J, Poulter, L. W (1998). Fluticasone propionate induced alterations to lung function and the immunopathology of asthma over time. Thorax 53: 753-761 [Abstract] [Full Text]  
• BARNES, P. J., PEDERSEN, S., BUSSE, W. W. (1998). Efficacy and Safety of Inhaled Corticosteroids . New Developments. Am. J. Respir. Crit. Care Med. 157: S1-53 [Full Text]  
• DUPONT, L. J., ROCHETTE, F., DEMEDTS, M. G., VERLEDEN, G. M. (1998). Exhaled Nitric Oxide Correlates with Airway Hyperresponsiveness in Steroid-naive Patients with Mild Asthma. Am. J. Respir. Crit. Care Med. 157: 894-898 [Abstract] [Full Text]  
• FABBRI, L. M., CARAMORI, G., BEGHÉ, B., PAPI, A., CIACCIA, A. (1997). Physiologic Consequences of Long-term Inflammation. Am. J. Respir. Crit. Care Med. 157: 195-198 [Full Text]