Biological clustering: new insights for the 'Dutch' versus 'British' hypotheses

Published Online: August 13, 2104

There remains an ongoing debate between the “Dutch hypothesis”, which proposes that asthma and chronic obstructive pulmonary disease (COPD) are manifestations of the same basic disease process, and the “British hypothesis”, which argues they are distinct entities generated by different mechanisms. This issue remains hotly debated particularly as we are entering a new era of molecular phenotyping and targeted biologic therapies, with a clamor for a new taxonomy of airway disease1. In an article recently published in The Journal of Allergy and Clinical Immunology, Ghebre and colleagues bring new insights, with biological clustering of asthma, and COPD using sputum mediator profiling2.

The authors compared the clinical, physiological characteristics and sputum mediators between 86 subjects with severe asthma, and 75 with moderate-to-severe COPD. Biological subgroups were determined on 18 sputum mediators. Critically, the clusters identified were validated in an independent similar-sized group of subjects with asthma or COPD. The authors found three biological clusters from sputum mediator profiles; cluster 1: asthma predominant, eosinophilic, high Th2 cytokines, which importantly also included 10% of the COPD subjects; cluster 2: asthma and COPD overlap, which clinically had chronic bronchitis, increased bacterial colonization, elevated sputum IL-1β and TNF-α and a sputum neutrophilia; cluster 3: COPD predominant, mixed eosinophilic and neutrophilic with elevated pro-inflammatory cytokines. Thus, this study suggests sputum inflammatory mediator profiling can determine distinct and overlapping groups of subjects with asthma and COPD—supporting both the “British” and “Dutch” hypotheses.

This study provides new insights into our understanding of the underlying distinct and overlapping biology of asthma and COPD, but perhaps more critically the clusters are likely to reflect groups that will have phenotype-specific treatment responses in those patients that are refractory to current therapies. For example, cluster 1 represents the group that is likely to respond to Th2-targeted therapy3,4, cluster 2 includes subjects that are likely to have a beneficial response to antibiotics5,6, and subjects in cluster 3 might respond to anti-inflammatory therapies directed towards modulating pro-inflammatory mediators. The importance of these biological clusters and the clinical importance of the “Dutch” versus “British” hypotheses will be fully realized with the insights to be learned from ongoing interventional studies of novel, highly-targeted small molecule and biologic therapies.

The Journal of Allergy and Clinical Immunology (JACI) is the official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

1. Vanfleteren L EGW, Kocks JWH, Stone IS, Breyer-Kohansal R, Greulich T, et al. Moving from the Oslerian paradigm to the post-genomic era: are asthma and COPD outdated terms? Thorax 2014;69: 72-79.

2. Ghebre MA, Bafadhel M, Desai D, Cohen SE, Newbold P, et al. Biological clustering supports both “Dutch” and “British” hypotheses of Asthma and Chronic Obstructive Pulmonary Disease. The Journal of Allergy and Clinical Immunology. 2014, in press.

3. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):651-9.

4. Brightling CE, Van Der Merwe R, She D, Birrell C. A Phase 2a Study Of Benralizumab, An Anti-Interleukin-5 Receptor Α Monoclonal Antibody, In Adults With Chronic Obstructive Pulmonary Disease And Sputum Eosinophilia. Am J Respir Crit Care Med 189;2014: A3771.

5. Brusselle GG, VanderStichele C, Jordens P, Deman R, Slabbynck H, Ringoet V, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68(4):322-9.

6. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JAD, Jr, Criner GJ, et al. Azithromycin for Prevention of Exacerbations of COPD. New England Journal of Medicine. 2011;365(8):689-98.

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