Hogg et al. (Citation1) were the first to report that the small conducting airways (mainly bronchioles) are the predominant site of airway narrowing in patients who smoke and develop COPD. Because of the large cross-sectional area available for airflow at this level of the tracheobronchial tree, substantial narrowing or obliteration of these small airways can occur before conventional measures of airflow obstruction and symptoms develop. Yet, this narrowing and loss of airways is largely irreversible so when the process finally manifests itself by a significant reduction of FEV1 or by breathlessness… the horse is out of the barn and it's too late to close the barn door.
This dilemma was recognized in 1970 by Jere Mead, who termed the small airways the lung's “quiet zone” (Citation2). A flurry of research activity ensued in an attempt to develop tests of small airway function that were sensitive to levels of obstruction or obliteration that were presymptomatic. The hope was for a test that could detect abnormal function in the airways prior to the onset of a decrease in FEV1. Such a test would allow the identification of a subset of smokers who had a preclinical stage of COPD and were therefore at risk for the eventual development of symptomatic disease. It was reasoned that intensive interventions in such individuals, such as smoking cessation campaigns, might be more effective than a program targeting all smokers.
The small airway tests that were developed included the measurement of the frequency dependence of dynamic compliance (Cdyn), the slope of phase 3 of the single-breath nitrogen washout (ΔN2/L), closing volume and closing capacity, the density dependence of maximal expiratory flow, and flows at lower lung volumes; FEF25–75 and the instantaneous forced expiratory flow rates at 50% and 25% of vital capacity. The basic premise was that the small airway tests would predict later decline in FEV1 because they were more sensitive than simple spirometry.
Unfortunately there is considerable evidence that this is incorrect. Changes in FEV1 and FEV1/forced vital capacity (FVC) parallel those in the small airway tests, (Citation3,4) and although the absolute changes in FEV1 may be less than those in small airway tests, they are of equal or greater significance because the coefficients of variation of FEV1 and FVC are much smaller. The results of longitudinal studies have, in general, not confirmed the hypothesis that abnormalities in small airway tests will predict longitudinal decline in FEV1 (Citation5,6). The horse was out of the barn! A more sensitive measure was needed.
Biomarkers to the rescue! In this issue of the Journal of Chronic Obstructive Pulmonary Disease, Bourdin and colleagues report the results of a search for a biomarker of small airway damage that would separate obstructed from non-obstructed smokers. As for those investigators who developed function tests for early detection, they reasoned that a biomarker might predict the susceptible smokers. They hypothesized that the ratio, in sputum, of the Clara cells-secreted protein (SCGB1A1), which has anti-inflammatory properties, and interleukin 18 (IL18) a marker of airway epithelial damage, might be sensitive to small airway dysfunction.
Despite a relatively small sample size they found that the ratio was strongly related to bronchiolar wall thickness (r = −0.83, p < 0.0001) and to a HRCT measure of small airway obstruction as well as to the slope of phase 3 of the single breath nitrogen washout. They concluded that the sputum SCGB1A1/IL8 ratio is a potentially valuable biomarker for non-invasive assessment of small airway disease in smokers.
Is this déjà vu all over again? The authors make no claim that their test will be predictive of the susceptible subset of smokers, but it is tempting to speculate that it might. Proof of any predictive value of the test will require longitudinal studies of non-selected smokers but a mechanistic biomarker is much more attractive as a predictive test than a lung function test of “early” disease since it may indicate that a process that leads to dysfunction is ongoing rather than has gone on. In addition the strength of the association raises the possibility that these markers, or more importantly their ratio, is involved in the causal pathway leading to airflow obstruction. As the authors state in their conclusion, “Whether smokers with high SCGB1A1/IL-8 levels could be better protected against COPD and whether exogenous SCGB1A1 supplementation could reverse those remodelling features will require further investigation in longitudinal study cohorts.” It will be exciting to see the results of such studies and find out if we can indeed keep the horse in the barn.
This issue also contains another study related to small airway disease in smokers. Kim et al. have investigated the long-standing observation that some subjects with COPD retain a degree of bronchodilator responsiveness while others do not. They reasoned that retention of bronchodilator responsiveness might be a biomarker of small airway disease. They made detailed measurements of small airway dimensions in the lungs of patients who had lung volume reduction surgery for advanced COPD and found that those with reproducible pre-operative bronchodilator responsiveness had thicker bronchiolar walls and an increased amount of airway smooth muscle.
There is increasing evidence that one can separate patients with COPD into those with emphysema predominant and airway disease using HRCT (Citation7), but this is the first study to show that bronchodilator responsiveness may also point to an airway predominant phenotype. The idea that increased airway smooth muscle mass and contractility might contribute to airway narrowing in COPD is not new. For example, Opazo-Saez et al. (Citation8) found that obstructed smokers had more and more contractile smooth muscle than non-obstructed smokers. However, the fact that a subset of smokers with advanced disease have increased muscle mass and that this can be detected by measuring bronchodilator responsiveness provides additional evidence for phenotypic heterogeneity in COPD. Phenotypic heterogeneity implies mechanistic heterogeneity and further supports the notion that individualized therapy rather than blanket therapy may be possible in COPD.
Declaration of interest
The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.
REFERENCES
- Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med 1968; 268:1355–1360.
- Mead J. The lung's “quiet zone”. N Engl J Med. 1970 Jun 4; 282(23):1318–1319.
- Dosman JA, Cotton DJ, Graham BL, Sensitivity and specificity of early diagnostic tests of lung function in smokers. Chest 1981; 79:6.
- Nemery B, Moavero NE, Brasseur L, Significance of small airway tests in middle-aged smokers. Am Rev Respir Dis 1981; 124:232.
- Olofsson J, Bake B, Svardsudd K, The single breath N2-test predicts the rate of decline in FEV1. Eur J Respir Dis 1986; 69:46–56.
- Buist AS, Vollmer WM, Johnson LR, Does the single-breath test identify the susceptible individual? Chest 1984;85:105.
- Patel BD, Coxson HO, Pillai SG, Agustí AG, Calverley PM, Donner CF, Make BJ, Müller NL, Rennard SI, Vestbo J, Wouters EF, Hiorns MP, Nakano Y, Camp PG, Nasute Fauerbach PV, Screaton NJ, Campbell EJ, Anderson WH, Paré PD, Levy RD, Lake SL, Silverman EK, Lomas DA; International COPD Genetics Network. Airway wall thickening and emphysema show independent familial aggregation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008 Sep 1;178(5):500–505.
- Opazo Saez AM, Seow CY, Paré PD. Peripheral airway smooth muscle mechanics in obstructive airways disease. Am J Respir Crit Care Med 2000 Mar;161(3 Pt 1):910–917.