Sputum colour in non-CF bronchiectasis: The original neutrophil biomarker

Non-cystic fibrosis bronchiectasis is characterised by neutrophil-driven airways inflammation leading to the clinical syndrome of cough, sputum production and recurrent respiratory infections. Historically, bronchiectasis has been an ‘orphan disease’ with a lack of research and few available treatments. The pathogenesis of bronchiectasis is traditionally viewed in terms of Coles' ‘vicious cycle’, linking airway structural damage (bronchiectasis), bacterial infection with opportunistic bacteria and airway inflammation, which then drives further structural damage and the continuation of the cycle.1, 2 Although this has been central to our understanding of bronchiectasis for decades, the scientific data to back up the interdependence of these three components of the cycle have been lacking.

There is particularly a need in bronchiectasis to identify patients in an ‘accelerated vicious cycle’ with progressive disease who are at high risk of deteriorating lung function, exacerbations, hospital admissions and death. At present, there are no validated disease severity tools or biomarkers for use in bronchiectasis.

Sputum colour has been a widely used indicator of airway inflammation and bacterial infection in bronchiectasis and other inflammatory lung diseases for generations, and few would view sputum colour as a ‘biomarker’.3 The National Institutes of Health, however, define a biomarker as ‘a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention’. Sputum colour correlates with markers of disease severity in stable patients and changes in sputum colour are part of the definition of exacerbations.4 Sputum colour changes in response to antibiotic therapy, therefore nicely meeting the definition of biomarker.5

The distinctive green colour of sputum in patients with bronchiectasis is the result of the accumulation of myeloperoxidase, a green haem-containing protein released from neutrophil primary granules as part of the process of killing phagocytosed bacteria. The accumulation of this protein in sputum is a very good indicator of the presence of activated neutrophils in the airway.3 Clear or white sputum typically indicates a relatively low number of inflammatory cells while an increase in sputum colour from pale green/yellow to dark green indicates the accumulation of larger numbers of neutrophils.

Sputum colour therefore represents a readily available and easily interpreted biomarker detecting the presence of inflammatory cells in the airway. Not only this, but since the primary driver for neutrophil recruitment to the airway appears to be bacteria, and neutrophil markers correlate closely with bacterial load, sputum colour also provides a rapid estimation of the presence of bacterial infection/colonisation.6

In this issue of Respirology, Goeminne et al. have sought to investigate the value of sputum colour as a marker of airway inflammation in bronchiectasis, presenting useful data that correlate sputum colour, inflammation, neutrophil protease activity and disease severity in a cohort of 49 patients with non-cystic fibrosis bronchiectasis.7

The study was based on the bronchiectasis specific colour chart developed by Murray,4 using photographs of patients sputum to classify patients into three broad categories: mucoid (white/clear—grade 1), mucopurulent (yellow/pale—grade 2) or purulent (green to dark green—grades 3 and 4). The chart shows excellent inter- and intraobserver reliability as well as correlating with important clinical measures such as high-resolution computed tomography appearance and the presence of bacterial infection.4

Goeminne et al. studied a cohort of patients with non-cystic fibrosis bronchiectasis due to a variety of causes and a control group of healthy volunteers matched for age and sex. The patient's disease severity was assessed using the Leicester Cough Questionnaire, Spirometry and a modified Brody score for high-resolution computed tomography scans. This latter feature is a particular strength of the Goeminne et al.'s study as most recent bronchiectasis studies have used a modified Reiff score, which only captures degree of dilatation and the number of lobes involved8 while the Brody score takes into account additional features including airway wall thickening, mucous plugging and parenchymal abnormalities.9

Patient's sputum was analysed for total cell count, inflammatory cytokines and total proteolytic activity, followed by the specific activity of individual proteases focussing on neutrophil elastase and matrix metalloproteinase-9.

The Murray colour chart proved to be an outstanding predictor of bacterial infection, with no patients with mucoid sputum being found to have bacterial infection by standard culture and also airway inflammation, correlating with total neutrophil counts and with protease activity.7

Proteases released from activated neutrophils appear to play a key role in disease progression in bronchiectasis.2 In this study, total protease activity in sputum correlated with forced expiratory volume in 1 s, forced vital capacity and high-resolution computed tomography scoring. Interestingly, there was no correlation between cough severity and protease activity, although whether this reflects the study sample size, the sensitivity of the Leicester cough questionnaire or a real disconnect between airway inflammation and cough requires further studies.

Goeminne et al. demonstrated that the majority of protease activity in the airway of the bronchiectasis patients was due to neutrophil elastase (82%). Elastase is a neutrophil enzyme of great importance as it has multiple damaging effects in the bronchiectasis airway including disabling phagocytes, promoting mucous hypersecretion, disrupting ciliary function and preventing the clearances of dead and dying cells.2 Larger studies are needed to determine if elastase may be useful marker to monitor disease progression, but it is clearly identified in this study, as with some previous studies, to be of great importance. Specific oral inhibitors of neutrophil elastase are currently in clinical trials for bronchiectasis.10

If sputum purulence is associated with proteolytic activity and bacterial infection, and this links to disease progression, what can we offer for the patient with green sputum? An increasing number of therapies are becoming available in bronchiectasis with evidence now supporting the use of oral macrolides, inhaled antibiotics and other therapies. Antibiotic therapy is highly effective in reducing both proteolytic activity and clearing sputum colour.5 Stratifying patients to identify those at risk of disease progression requiring prolonged antibiotic or anti-inflammatory therapies is vital, while keeping in mind the potential side effects and the threat of antimicrobial resistance that accompany these treatments. Until better biomarkers are available, sputum colour is our only direct measure of airway inflammation in routine practice—the original biomarker, and should be part of a global assessment of which patients require aggressive treatment.