Respiratory Diseases

The airways diseases asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous and complex diseases associated with immune dysfunction and consequent significant morbidity, mortality and healthcare expense. There are approximately 350 million people with asthma and 400 million with COPD worldwide. COPD is predicted to become the 3rd leading cause of death worldwide by 2030. The increasing recognition of disease heterogeneity in asthma and COPD with consequent variable responses to therapy highlights the need to further investigate the underlying pathophysiology, environmental triggers and therapeutic response.

• Current Challenges related to biomarker development

  The challenge for airways disease is to be able to prevent exacerbations, induce remission and cure disease. In those with established disease the aim is control of symptoms, reduce attacks and ultimately to modify disease by inducing remission and possibly cure. There have been notable successes in identification of biomarkers in airways disease associated with specific phenotypes that when applied to groups of patients can predict increased likelihood of response. However, at an individual level we have a limited ability to reliably predict the natural history of airways disease and therefore are poor at predicting future disease control and risk of attacks.

  One of the challenges with trying to develop biomarkers for response to therapy is that markers of response might be infrequent such as attacks, insensitive such as current tools for assessing disease control and health status or not perceived by patients such as progressive lung function decline. Thus, there is a tremendous need for a better understanding of response from patients’ perspectives as well as through a greater understanding of the disease mechanisms in order to develop biomarkers with improved clinical utility.

• Central findings with regard to immune response

  One of the greatest achievements in the last 20 years in airways disease research has been the detailed dissection of the innate and adaptive immune responses and their consequent inflammatory profiles in the airway in response to triggers such as allergens, microbes and pollution. Particularly in asthma this has uncovered key mechanisms driving type-2 cytokine mediated responses and has led to the successful adoption of new biologics targeting T2-mediated immunity in the clinic namely targeting immunoglobulin (Ig)E, the IL-5 pathways. With recent success of anti-IL4Rα in phase 3 and other biologics and small molecules in late phase development it is likely that several other drug classes will soon be available to treat airways disease.

  The success in clinical trials in asthma has largely been due to the recognition that these mechanisms are of greatest importance in severe disease and in driving asthma attacks. The implementation of measuring blood and sputum eosinophil counts and the assessment of fractional exhaled nitric oxide has provided key type-2 associated biomarkers of T2-disease activity and can be used as diagnostic, prognostic and theranostic biomarkers. In COPD, the importance of the immune component is well-recognized in relation to an abnormal inflammatory response to tobacco smoke leading to persistent pulmonary and systemic inflammation, the exacerbations of the disease, and autoimmunity contributing to the development of emphysema.

  However, in contrast to asthma the response to biologics (i.e. anti-IL-1β, TNF, IL-13 and IL-5) has been poor suggesting either these interventions are ineffective in COPD or that patient selection needs to be optimised. Thus, to address this challenge improved coupling of biomarkers that capture information about airway inflammation and immunity but also changes in airway structure and function assessed by lung physiology and imaging to clinical outcomes is key to improve our ability to predict response.