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Original Research: ASTHMA |

Association Between Neutrophilic Airway Inflammation and Airflow Limitation in Adults With Asthma* FREE TO VIEW

Dominick E. Shaw, MRCP; Michael A. Berry, MD, MRCP; Bev Hargadon, RN; Susan McKenna, RGN; Maria J. Shelley, BA; Ruth H. Green, MD, FRCP; Christopher E. Brightling, PhD, FRCP; Andrew J. Wardlaw, PhD, FRCP; Ian D. Pavord, DM, FRCP
Author and Funding Information

*From the Institute for Lung Health, Department of Respiratory Medicine and Thoracic Surgery, Glenfield Hospital, Leicester, UK.

Correspondence to: Dominick E. Shaw, MRCP, Institute for Lung Health, Department of Respiratory Medicine and Thoracic Surgery, Glenfield Hospital, Leicester LE3 9QP, UK; e-mail: dominickshaw@doctors.org.uk



Chest. 2007;132(6):1871-1875. doi:10.1378/chest.07-1047
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Published online

Background: There is debate about the mechanisms of persistent airflow limitation in patients with asthma. Chronic inflammation is assumed to be important, although there is limited and contradictory information about the relationship between airway inflammation and postbronchodilator FEV1.

Methods: We have assessed the cross-sectional relationship between prebronchodilator and postbronchodilator FEV1 and measures of airway inflammation after allowing for the effects of potential confounding factors. Multivariate analysis was performed on data collected from 1,197 consecutive patients with asthma seen at the respiratory outpatient clinic at Glenfield Hospital between 1997 and 2004. Relationships between induced sputum total neutrophil and differential eosinophil cell counts, and prebronchodilator and postbronchodilator lung function were examined.

Results: Sputum total neutrophil but not differential eosinophil count was associated with lower postbronchodilator FEV1. Both differential eosinophil and total neutrophil count were associated with lower prebronchodilator FEV1. These effects were independent after adjustment for age, smoking, ethnicity, asthma duration, and inhaled corticosteroid use. A 10-fold increase in neutrophil count was associated with a 92 mL reduction (95% confidence interval, 29 to 158; p = 0.007) in postbronchodilator FEV1.

Conclusions: In this large heterogeneous population of adults with asthma, we have shown that prebronchodilator FEV1 is associated with neutrophilic and eosinophilic airway inflammation, whereas sputum total neutrophil counts alone are associated with postbronchodilator FEV1. This supports the hypothesis that neutrophilic airway inflammation has a role in the progression of persistent airflow limitation in asthma and raises the possibility that this progression and the development of COPD share a common mechanism.

Asthma has been associated with an increased rate of decline in lung function: in a 15-year follow-up study by Lange et al,1adults with asthma showed a greater decline in lung function than those without the disease, with an unadjusted loss of 38 mL/yr occurring in patients with asthma, compared to a loss of 22 mL/yr in control subjects. One goal of asthma management is to stop long-term respiratory disability by preventing this loss of lung function, so a clearer understanding of the mechanisms involved in the development of fixed airflow obstruction is important. Factors that have been associated with an increased rate of decline include smoking,2 duration of asthma,2and absence of atopy.3Chronic airway inflammation is widely assumed to be important in the genesis of fixed airflow obstruction, although previous studies47 examining the relationship between airway inflammation and postbronchodilator FEV1 have produced conflicting results.

ten Brinke et al7showed that the only independent factor associated with persistent airflow limitation was a differential sputum eosinophilia, whereas Woodruff et al8 demonstrated that raised differential sputum eosinophil and neutrophil counts were both associated with a lower prebronchodilator FEV1. One difficulty of studies of this kind is that definition of best FEV1 is imprecise in a condition that is associated with variable airflow obstruction, although increasing study numbers might allow important relationships to become apparent. We set out to investigate the relationship between prebronchodilator and postbronchodilator FEV1 and measurements of eosinophilic and neutrophilic airway inflammation in a large, well-characterized population of adults with asthma.

Subjects

A total of 1,197 consecutive patients seen in the respiratory outpatient clinic at Glenfield Hospital between November 1997 and March 2004 were included in the study. Glenfield Hospital is a secondary care facility covering a population of 1 million people of mixed ethnicity and social class. The main indications for referral for assessment of airway disease were diagnostic uncertainty and poor symptom control. Informed consent for the assessment of airway inflammation was obtained for all patients as part of the clinical assessment of airway disease, and the ethics committee from the University Hospitals of Leicester gave ethical approval for the study. All subjects had symptoms of asthma and objective evidence of airway hyperresponsiveness and/or variable airflow obstruction as demonstrated by one or more of the following: a provocative concentration of methacholine causing a > 20% fall in FEV1 (PC20) < 8 mg/mL; an increase in FEV1 ≥ 15% 20 min after inhalation of 200 μg of albuterol; or peak expiratory flow variability > 20% of mean based on peak expiratory flow recorded twice daily over a 2-week period. Methacholine challenge was not performed if FEV1 was < 70% of predicted. In this situation, patients were included if they had a > 15% improvement in FEV1 20 min after bronchodilator. Atopy was defined as a wheal 2 mm greater than control on skin-prick testing or specific IgE (Pharma CAP; ALK-Abelló; Madrid, Spain) to one or more of dust mite, grass, tree, cat, dog, or Aspergillus allergens. Smoking history was recorded as pack-years and was validated against other hospital or primary care records or exhaled carbon monoxide monitoring if there was doubt about its veracity.

Measurements

Spirometry was performed using a spirometer (Vitalograph; Vitalograph Ltd; Maids Moreton, UK) as the best of three consecutive readings within 100 mL, and skin-prick tests were performed using standard techniques.9Prebronchodilator and postbronchodilator measurements were recorded 20 min after the inhalation of 200 μg of albuterol via spacer. Induced sputum was obtained and processed as previously described.10Methacholine challenge was performed using a Wright nebulizer (Aerosol Medical Ltd; Colchester, UK) and the Juniper tidal breathing method.11

Protocol

At the first visit, patients underwent spirometry, methacholine challenge testing, sputum induction, skin-prick testing, and measurement of specific IgE to common aeroallergens; history of cigarette smoking and duration of symptoms were recorded. At the next visit, prebronchodilator and postbronchodilator FEV1 values were recorded.

Analysis

Eosinophil counts were expressed as a percentage of nonsquamous cells because eosinophil differential counts are log-normally distributed.10,1213 Neutrophil counts were expressed as the total number of neutrophils per gram of sputum. Neutrophil counts were expressed in this way because sputum differential neutrophil counts increase with age,14have a biphasic distribution in our population, and because increases in neutrophilic airway inflammation are better reflected by the total neutrophil count rather than the differential.15 Multiple independent regressions were used to identify predictors of postbronchodilator and prebronchodilator FEV1. We also performed backward stepwise linear regression to further identify independent associations. Age, height, gender, and ethnic origin are known to be associated with these outcomes and were therefore included in the model. Total neutrophil counts and percentage eosinophil counts were log-transformed prior to analysis to fulfil the model assumption of normal distribution. Atopy and inhaled corticosteroid (ICS) use were considered potential confounders and were entered into the models as binary variables. Duration of asthma symptoms was also considered a possible cofactor and was entered as a continuous variable. All analysis was performed using statistical software (SPSS 10 for Windows; SPSS; Chicago, IL).

Patient demographics are given in Table 1 .

Postbronchodilator FEV1

Postbronchodilator FEV1 was significantly predicted by this model (Table 2 ) [R2 = 0.43, p < 0.001]. ICS use was associated with a lower postbronchodilator FEV1 by 223 mL on average (95% confidence interval [CI], 93 to 354 mL; p < 0.001) compared with corticosteroid-naïve patients. Postbronchodilator FEV1 was 15 mL lower per pack-year smoked (95% CI, 9 to 20 mL; p < 0.001) and 7 mL lower per year of asthma (95% CI, 3 to 11 mL; p < 0.001). Sputum neutrophil count was associated with a 92-mL reduction in postbronchodilator FEV1 per 10-fold rise in total sputum neutrophil count per milligram (95% CI, 26 to 158 mL; p < 0.007). Sputum eosinophil count and atopy did not independently predict postbronchodilator FEV1. The association between postbronchodilator FEV1 and sputum total neutrophil count was unchanged in the backward stepwise linear regression.

Prebronchodilator FEV1

Prebronchodilator FEV1 was significantly predicted by this model (Table 3 ) [R2 = 0.39, p < 0.001]. ICS use was associated with a lower prebronchodilator FEV1 when compared with corticosteroid-naïve patients. Prebronchodilator FEV1 was reduced by 14 mL per pack-year smoked (95% CI, 8 to 19 mL; p < 0.001) and 9 mL per year of asthma symptoms (95% CI, 5 to 13 mL; p < 0.001). Sputum neutrophil count was associated with an 83-mL reduction in prebronchodilator FEV1 per 10-fold rise in total neutrophil count per gram (95% CI, 15 to 152 mL; p < 0.017) and sputum eosinophil count predicted a 116-mL-lower prebronchodilator FEV1 per 10-fold increase in percentage eosinophil count (95% CI, 49 to 183 mL; p < 0.001). Atopy did not independently predict prebronchodilator FEV1. The associations between prebronchodilator FEV1 and sputum total neutrophil count and differential eosinophil count were unchanged in the backward stepwise linear regression.

We have shown a weak relationship between prebronchodilator and postbronchodilator FEV1 and sputum measures of airway inflammation in a large heterogeneous population of adults with asthma. Postbronchodilator FEV1 was associated with sputum total neutrophil count. Smoking, ICS use, and asthma duration were also associated with a lower postbronchodilator FEV1. A raised sputum neutrophil count was associated with a lower prebronchodilator FEV1 but to a lesser extent than the differential sputum eosinophil count, where a 10-fold increase in eosinophil percentage was associated with a 116-mL-lower prebronchodilator FEV1.

Woodruff et al8 have also demonstrated a relationship between airway neutrophilia and persistent airflow limitation in asthma. They used multivariate analysis of data collected during screening and enrolment of 205 adults with asthma. After controlling for confounding factors, their analysis demonstrated that eosinophil percentage in induced sputum was independently associated with a lower FEV1 and a lower PC20. In the same models, an increased sputum neutrophil percentage was independently associated with lower FEV1 but not with PC20. These results suggest that both eosinophilic inflammation and neutrophilic inflammation independently contribute to abnormalities of FEV1 in asthma. A study by Little et al,16 also demonstrated that maximal FEV1 was inversely associated with duration of disease and differential sputum neutrophil count. Our findings and the findings of earlier studies would be consistent with a model in which eosinophilic airway inflammation contributes to variable airflow obstruction and airway hyperresponsiveness, and neutrophilic inflammation contributes to irreversible airflow obstruction in asthma.,16However, one small, longitudinal bronchoscopy study17 found that eosinophil counts in bronchial biopsies did not correlate with either prebronchodilator or postbronchodilator FEV1. This may reflect the different lung compartment sampled in bronchial biopsy as compared to induced sputum.

Our findings differ from those of ten Brinke et al,7 who found that of age at onset, smoking history, atopic status, bronchodilator reversibility, provocative concentration of histamine causing a 20% fall in FEV1, exhaled nitric oxide, blood eosinophils, and total IgE, the only independent factor associated with persistent airflow limitation was sputum eosinophilia. This was a smaller homogeneous population with a more limited analysis of dichotomous variables; 132 nonsmoking asthmatics receiving high-dose ICS were studied, and persistent airflow limitation was defined as a postbronchodilator FEV1 or FEV1/FVC < 75% of predicted. The association was not apparent in the subgroup receiving oral corticosteroids, suggesting that the patients receiving ICS may have been undertreated.

We evaluated patients referred to secondary care for investigation of poor symptom control or because of diagnostic uncertainty. All had symptoms consistent with asthma and objective evidence of variable airflow obstruction. However, we recognize that the population studied may not be representative of the wider population with asthma, and our study should be interpreted in this light. Patients were not assessed at the time of exacerbation or within 1 month of an exacerbation, but we did not collect information on the time of the last exacerbation, so it is possible that effect of a more distant exacerbation may have affected airway inflammation. This was a large study, so it was not possible to collect data on other variables of potential importance, including occupational dust exposure, time of last cigarette, or exact treatment dose and duration. It was also not possible to perform complex analysis of cell-activation markers on induced-sputum supernatant. Further studies should evaluate this. Bias caused by treatment, varying sputum induction time, and prior methacholine challenge is unlikely to account for our findings because corticosteroids and long-acting β2-agonists do not influence sputum neutrophil counts significantly,1819 we were careful to standardize sputum induction time, and there is no evidence that prior methacholine challenge affects sputum cell counts.20

Our findings are consistent with the view that neutrophilic airway inflammation contributes to the development of fixed airflow obstruction in asthma, although we recognize that a cross-sectional analysis such as this cannot prove a causal relationship. However, there are several lines of evidence to suggest that the relationship we have seen is real. Firstly, our findings are consistent with those of several previous, smaller studies.8,16,21Secondly, the relationship between neutrophilic airway inflammation and progressive airflow obstruction is biologically plausible because neutrophils can secrete a variety of inflammatory factors including cytokines, proteases, and lung parenchymal reactive oxygen species that can cause mucus hypersecretion and airway damage. Thirdly, our findings are consistent with increasing evidence implicating neutrophilic inflammation in severe asthma,22 a phenotype that is particularly associated with fixed airflow obstruction.6

One of the difficulties of a study investigating progressive airflow obstruction in asthma is the definition of best achievable FEV1.We recognize that some patients may have had important improvement in FEV1 with more intensive corticosteroid therapy. However, improvement in FEV1 following corticosteroid treatment is associated with an increase in the sputum eosinophil count but not sputum neutrophils,23 so this factor is unlikely to have influenced the relationship between sputum neutrophils and postbronchodilator FEV1. In keeping with this view, Little et al,16 have shown that an increase in sputum neutrophils is associated with lower postbronchodilator, post-oral corticosteroid FEV1.

Previous studies2425 have demonstrated a consistent cross-sectional relationship between sputum neutrophils and postbronchodilator FEV1 in COPD. Moreover, the rate of decline in FEV1 in subjects with COPD is associated with the sputum neutrophil count.26 These findings raise the possibility that the mechanisms of development of progressive fixed airflow obstruction in asthma and COPD have some similarities. Further study of these mechanisms is potentially clinically important because there is no evidence that the neutrophilic small airway inflammatory response thought to be important in the pathogenesis of COPD is corticosteroid responsive.27

Abbreviations: CI = confidence interval; ICS = inhaled corticosteroid; PC20 = provocative concentration of methacholine causing a 20% fall in FEV1

The authors have no conflicts of interest to disclose.

Dr. Shaw has received a travel grant from GlaxoSmithKline and lecture fees from Astra-Zeneca. Dr. Berry has received a travel grant from GlaxoSmithKline. Dr. Brightling has received lecture fees from Astra-Zeneca and GlaxoSmithKline and a research grant from Cambridge antibody technology. Dr. Wardlaw has received lecture fees from Altana pharmaceuticals and MSD and research grants from Wyeth, Astra-Zeneca, and GlaxoSmithKline. Dr. Pavord has received lecture fees and research grants from Astra-Zeneca and GSK.

Table Graphic Jump Location
Table 1. Patient Characteristics*
* 

Data are presented as mean (SE of mean) unless otherwise indicated.

 

Data are presented as geometric mean (log SE of mean).

Table Graphic Jump Location
Table 2. Model for Dependent Variable: Postbronchodilator FEV1
Table Graphic Jump Location
Table 3. Model for Dependent Variable: Prebronchodilator FEV1
Lange, P, Parner, J, Vestbo, J, et al (1998) A 15-year follow-up study of ventilatory function in adults with asthma.N Engl J Med339,1194-1200. [PubMed] [CrossRef]
 
Sears, MR Consequences of long-term inflammation: the natural history of asthma.Clin Chest Med2000;21,315-329. [PubMed]
 
Ulrik, CS, Backer, V, Dirksen, A A 10 year follow up of 180 adults with bronchial asthma: factors important for the decline in lung function.Thorax1992;47,14-18. [PubMed]
 
Bousquet, J, Chanez, P, Lacoste, JY, et al Eosinophilic inflammation in asthma.N Engl J Med1990;323,1033-1039. [PubMed]
 
Djukanovic, R, Roche, WR, Wilson, JW, et al Mucosal inflammation in asthma.Am Rev Respir Dis1990;142,434-457. [PubMed]
 
Wenzel, SE, Schwartz, LB, Langmack, EL, et al Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics.Am J Respir Crit Care Med1999;160,1001-1008. [PubMed]
 
ten Brinke, A, Zwinderman, AH, Sterk, PJ, et al Factors associated with persistent airflow limitation in severe asthma.Am J Respir Crit Care Med2001;164,744-748. [PubMed]
 
Woodruff, PG, Khashayar, R, Lazarus, SC, et al Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma.J Allergy Clin Immunol2001;108,753-758. [PubMed]
 
Dreborg, S The skin prick test in the diagnosis of atopic allergy.J Am Acad Dermatol1989;21,820-821. [PubMed]
 
Pavord, ID, Pizzichini, MM, Pizzichini, E, et al The use of induced sputum to investigate airway inflammation.Thorax1997;52,498-501. [PubMed]
 
Sterk, PJ, Fabbri, LM, Quanjer, PH, et al Airway responsiveness: standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults: report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal; official statement of the European Respiratory Society.Eur Respir J Suppl1993;16,53-83. [PubMed]
 
Belda, J, Leigh, R, Parameswaran, K, et al Induced sputum cell counts in healthy adults.Am J Respir Crit Care Med2000;161,475-478. [PubMed]
 
Spanevello, A, Confalonieri, M, Sulotto, F, et al Induced sputum cellularity: reference values and distribution in normal volunteers.Am J Respir Crit Care Med2000;162,1172-1174. [PubMed]
 
Thomas, RA, Green, RH, Brightling, CE, et al The influence of age on induced sputum differential cell counts in normal subjects.Chest2004;126,1811-1814. [PubMed]
 
Neale, N, Parker, D, Barlow, S, et al The relationship between total and differential cell counts in induced sputum [abstract].Eur Respir J2002;20,274s
 
Little, SA, MacLeod, KJ, Chalmers, GW, et al Association of forced expiratory volume with disease duration and sputum neutrophils in chronic asthma.Am J Med2002;112,446-452. [PubMed]
 
van Rensen, EL, Sont, JK, Evertse, CE, et al Bronchial CD8 cell infiltrate and lung function decline in asthma.Am J Respir Crit Care Med2005;172,837-841. [PubMed]
 
Berry, MA, Morgan, A, Shaw, DE, et al Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax. 2007; ;
 
Green, RH, Brightling, CE, Woltmann, G, et al Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids.Thorax2002;57,875-879. [PubMed]
 
Spanevello, A, Vignola, AM, Bonanno, A, et al Effect of methacholine challenge on cellular composition of sputum induction.Thorax1999;54,37-39. [PubMed]
 
Woodruff, PG, Fahy, JV A role for neutrophils in asthma?Am J Med2002;112,498-500. [PubMed]
 
The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma.Eur Respir J2003;22,470-477. [PubMed]
 
Pavord, ID, Brightling, CE, Woltmann, G, et al Non-eosinophilic corticosteroid unresponsive asthma.Lancet1999;353,2213-2214. [PubMed]
 
Perng, DW, Huang, HY, Chen, HM, et al Characteristics of airway inflammation and bronchodilator reversibility in COPD: a potential guide to treatment.Chest2004;126,375-381. [PubMed]
 
Peleman, RA, Rytila, PH, Kips, JC, et al The cellular composition of induced sputum in chronic obstructive pulmonary disease.Eur Respir J1999;13,839-843. [PubMed]
 
Stanescu, D, Sanna, A, Veriter, C, et al Airways obstruction, chronic expectoration, and rapid decline of FEV1in smokers are associated with increased levels of sputum neutrophils.Thorax1996;51,267-271. [PubMed]
 
Brightling, CE, Monteiro, W, Ward, R, et al Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial.Lancet2000;356,1480-1485. [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1. Patient Characteristics*
* 

Data are presented as mean (SE of mean) unless otherwise indicated.

 

Data are presented as geometric mean (log SE of mean).

Table Graphic Jump Location
Table 2. Model for Dependent Variable: Postbronchodilator FEV1
Table Graphic Jump Location
Table 3. Model for Dependent Variable: Prebronchodilator FEV1

References

Lange, P, Parner, J, Vestbo, J, et al (1998) A 15-year follow-up study of ventilatory function in adults with asthma.N Engl J Med339,1194-1200. [PubMed] [CrossRef]
 
Sears, MR Consequences of long-term inflammation: the natural history of asthma.Clin Chest Med2000;21,315-329. [PubMed]
 
Ulrik, CS, Backer, V, Dirksen, A A 10 year follow up of 180 adults with bronchial asthma: factors important for the decline in lung function.Thorax1992;47,14-18. [PubMed]
 
Bousquet, J, Chanez, P, Lacoste, JY, et al Eosinophilic inflammation in asthma.N Engl J Med1990;323,1033-1039. [PubMed]
 
Djukanovic, R, Roche, WR, Wilson, JW, et al Mucosal inflammation in asthma.Am Rev Respir Dis1990;142,434-457. [PubMed]
 
Wenzel, SE, Schwartz, LB, Langmack, EL, et al Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics.Am J Respir Crit Care Med1999;160,1001-1008. [PubMed]
 
ten Brinke, A, Zwinderman, AH, Sterk, PJ, et al Factors associated with persistent airflow limitation in severe asthma.Am J Respir Crit Care Med2001;164,744-748. [PubMed]
 
Woodruff, PG, Khashayar, R, Lazarus, SC, et al Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma.J Allergy Clin Immunol2001;108,753-758. [PubMed]
 
Dreborg, S The skin prick test in the diagnosis of atopic allergy.J Am Acad Dermatol1989;21,820-821. [PubMed]
 
Pavord, ID, Pizzichini, MM, Pizzichini, E, et al The use of induced sputum to investigate airway inflammation.Thorax1997;52,498-501. [PubMed]
 
Sterk, PJ, Fabbri, LM, Quanjer, PH, et al Airway responsiveness: standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults: report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal; official statement of the European Respiratory Society.Eur Respir J Suppl1993;16,53-83. [PubMed]
 
Belda, J, Leigh, R, Parameswaran, K, et al Induced sputum cell counts in healthy adults.Am J Respir Crit Care Med2000;161,475-478. [PubMed]
 
Spanevello, A, Confalonieri, M, Sulotto, F, et al Induced sputum cellularity: reference values and distribution in normal volunteers.Am J Respir Crit Care Med2000;162,1172-1174. [PubMed]
 
Thomas, RA, Green, RH, Brightling, CE, et al The influence of age on induced sputum differential cell counts in normal subjects.Chest2004;126,1811-1814. [PubMed]
 
Neale, N, Parker, D, Barlow, S, et al The relationship between total and differential cell counts in induced sputum [abstract].Eur Respir J2002;20,274s
 
Little, SA, MacLeod, KJ, Chalmers, GW, et al Association of forced expiratory volume with disease duration and sputum neutrophils in chronic asthma.Am J Med2002;112,446-452. [PubMed]
 
van Rensen, EL, Sont, JK, Evertse, CE, et al Bronchial CD8 cell infiltrate and lung function decline in asthma.Am J Respir Crit Care Med2005;172,837-841. [PubMed]
 
Berry, MA, Morgan, A, Shaw, DE, et al Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax. 2007; ;
 
Green, RH, Brightling, CE, Woltmann, G, et al Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids.Thorax2002;57,875-879. [PubMed]
 
Spanevello, A, Vignola, AM, Bonanno, A, et al Effect of methacholine challenge on cellular composition of sputum induction.Thorax1999;54,37-39. [PubMed]
 
Woodruff, PG, Fahy, JV A role for neutrophils in asthma?Am J Med2002;112,498-500. [PubMed]
 
The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma.Eur Respir J2003;22,470-477. [PubMed]
 
Pavord, ID, Brightling, CE, Woltmann, G, et al Non-eosinophilic corticosteroid unresponsive asthma.Lancet1999;353,2213-2214. [PubMed]
 
Perng, DW, Huang, HY, Chen, HM, et al Characteristics of airway inflammation and bronchodilator reversibility in COPD: a potential guide to treatment.Chest2004;126,375-381. [PubMed]
 
Peleman, RA, Rytila, PH, Kips, JC, et al The cellular composition of induced sputum in chronic obstructive pulmonary disease.Eur Respir J1999;13,839-843. [PubMed]
 
Stanescu, D, Sanna, A, Veriter, C, et al Airways obstruction, chronic expectoration, and rapid decline of FEV1in smokers are associated with increased levels of sputum neutrophils.Thorax1996;51,267-271. [PubMed]
 
Brightling, CE, Monteiro, W, Ward, R, et al Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial.Lancet2000;356,1480-1485. [PubMed]
 
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