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Leicester, UK
Dr. Brightling is affiliated with the Institute for Lung Health, Department of Infection, Inflammation and Immunity, University of Leicester.
Correspondence to: Christopher E. Brightling, PhD, FCCP, Department of Respiratory Medicine, University Hospitals of Leicester, Groby Rd, Leicester, LE3 9QP, UK; e-mail: ceb17{at}le.ac.uk
A Research Technique or a Clinical Tool?
Clinicians have been interested in the study of sputum in asthma patients since the end of the 19th century when Curshman spirals and Charcot-Leyden crystals were first described as being associated with sputum eosinophilia. However, sputum analysis was initially hampered as an investigative tool by a lack of standardization and the inability to obtain a sample in many cases. In the last 15 to 20 years, this problem has been overcome by inducing sputum using hypertonic saline solution, a technique that is safe and reproducible. Good-quality cytospins can be routinely obtained, and a reliable differential cell count can be generated.1
The increasing application of this technique has led to the recognition that inflammation in asthma patients is more heterogeneous than was previously thought with the identification of noneosinophilic asthma.234 This phenotype is common, accounting for 25 to 55% of patients with corticosteroid-naive asthma, and is repeatable, with few subjects with noneosinophilic asthma developing airway eosinophilia during follow-up for 1 year.5 This asthma phenotype is not reserved to patients with severe asthma, nor is it a consequence of asthma therapy, but it is present across the range of asthma severity.4 Its identification is important as it is related to a poor response to corticosteroids.2 This view is supported by a study reported in this edition of CHEST (see page 565) by Bacci et al,6 who studied a group of 67 symptomatic asthmatic patients before and 2 and 4 weeks after receiving therapy with inhaled beclomethasone dipropionate, 500 µg twice daily. A total of 17 patients (25%) had noneosinophilic asthma. Consistent with previous studies,27 they found that a sputum eosinophil count, but not other markers of inflammation in sputum or peripheral blood, correlated with changes in lung function after corticosteroid treatment. One shortcoming of this study was its open-label design. However, in support of the findings of Bacci et al,6 a placebo-controlled cross-over trial7 of inhaled mometasone, 400 µg once daily for 8 weeks, in subjects who were characterized as having either eosinophilic or noneosinophilic asthma prior to study entry confirmed that a favorable response to corticosteroids is reserved for asthmatic patients with sputum eosinophilia.
In addition to asthma phenotype, smoking status has also been proposed to influence corticosteroid responsiveness in asthma. A series of reports from Glasgow (see the review by Thomson and Spears9) has suggested that smoking confers a relative corticosteroid resistance. However, work from the same group10 found that asthmatic patients who smoked did not have sputum eosinophilia. The study by Bacci et al6 included ex-smokers and current smokers. They found that smoking status per se was not associated with a poor response to corticosteroids, but that in subjects who smoked the presence or absence of sputum eosinophilia remained the best predictor of the response to treatment with corticosteroids. This observation is important as it suggests that the poor response to corticosteroids reported in asthmatic patients who smoke might reflect an absence of a corticosteroid-responsive pathology.
Importantly, the value of measuring airway inflammation in sputum extends beyond these relatively short-term studies on corticosteroid responsiveness. In a randomized placebo-controlled trial,5 74 subjects with asthma were assigned to either a management strategy aimed at normalizing their sputum eosinophil count or standard clinical care. Patients in the sputum management group experienced significantly fewer severe asthma exacerbations than patients in the control group (35 vs 109 patients, respectively; p = 0.01) and significantly fewer patients were admitted to the hospital with asthma (1 vs 6 patients, respectively; p = 0.047). There were no significant differences in the average daily dose of inhaled or oral corticosteroids between the two groups. A reduction in the number of exacerbations was achieved without an increase in the total corticosteroid dose in the sputum guidelines group, as monitoring airway inflammation in the sputum guidelines group identified a group of patients with noneosinophilic asthma whose sputum eosinophil count remained within the normal range. In these subjects, the dose of corticosteroids was reduced without evidence of deterioration in the control of asthma.
Economic analysis shows that the health-care-related savings occurring as a consequence of the reduction in the number of asthma exacerbations outweighs the cost of sputum induction and processing.5 This supports a role for this test to be routine in specialist centers. However, sputum induction is labor-intensive and requires laboratory support. Thus, for these reasons it is unlikely that this method could be extrapolated to a primary care setting. Thus, there is a need for a simpler method to identify sputum eosinophilia. Alternatively, the assessment of exhaled gases, such as exhaled nitric oxide, provides a simple measure that can be undertaken in the primary care setting. However, asthma management strategies that use the measurement of exhaled nitric oxide to guide treatment with corticosteroids have not been able to alter exacerbation rates.1112
In conclusion, the measurement of a sputum eosinophil count has value in predicting the response to corticosteroids, and the regular monitoring of airway inflammation is an important facet of optimal asthma management. Therefore, sputum induction as a useful research technique is not in doubt, but its potential role in the clinic is yet to be realized.
Footnotes
Dr. Brightling has no conflict of interest to disclose.
References
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