Review Allergy Asthma Immunol Res. 2014 September;6(5):376-388. http://dx.doi.org/10.4168/aair.2014.6.5.376 pISSN 2092-7355 • eISSN 2092-7363 Small Airways Dysfunction in Asthma: Evaluation and Management to Improve Asthma Control Omar S Usmani* Airway Disease Section, National Heart and Lung Institute, Imperial College London & Royal Brompton Hospital, London, UK This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The small airways have been neglected for many years, but interest in the topic has been rekindled with recent advances in measurement tech- niques to assess this region and also the ability to deliver therapeutics to the distal airways. Current levels of disease control in asthmatic patients remain poor and there are several contributory factors including; poor treatment compliance, heterogeneity of asthma phenotypes and associated comorbidities. However, the proposition that we may not be targeting all the inflammation that is present throughout the whole respiratory tree may also be an important factor. Indeed decades ago, pathologists and physiologists clearly identified the importance of small airways dysfunction in asthmatic patients. With improved inhaler technology to deliver drug to target the whole respiratory tree and more sensitive measures to assess the distal airways, we should certainly give greater consideration to treating the small airway region when seeing our asthmatic patients in clinic. The aim of this review is to address the relevance of small airways dysfunction in the daily clinical management of patients with asthma. In particular the role of small particle aerosols in the management of patients with asthma will be explored. Key Words: Small airways; asthma; physiology; pharmacology; inhalation; aerosols; corticosteroids; long-acting beta agonists INTRODUCTION have been many terms used to describe these aerosols, for the purposes of this review small particle aerosols are defined as There have been many reviews published recently in the last those ≤2 microns in diameter. The manuscript was a review of few years on small airways dysfunction and its importance in the literature using keywords of small airways; asthma; physiol- respiratory disease, particularly in asthma, as interest in this ogy; pharmacology; inhalation; aerosols; corticosteroids; long- topic has be rekindled by advances in measurement tech- acting beta agonists; medication. niques of, and therapeutic delivery to, the peripheral lung re- gions.1-4 This review attempts to approach the topic in a differ- Asthma control is still not optimal ent manner. It will address the significance of small airways The last three decades have seen important advances in the dysfunction in the daily clinical management of patients with management of patients with asthma and these include; great- asthma and in particular, the literature will be reviewed to help er awareness and timely diagnosis of the disease, pharmaco- answer the following pragmatic questions to inform the busy logical interventions principally targeted at controlling the un- practicing respiratory healthcare professional in clinic. derlying airways inflammation, the realisation of and appropri- ate management of the significant comorbidities associated 1. Is small airways dysfunction relevant in the asthmatic pa- with the condition, and a multidisciplinary approach to care for tient? 2. If so, how can we target drug to treat small airways dysfunc- tion? Correspondence to: Omar S Usmani, MD, PhD, Airway Disease Section, Guy 3. Does treatment of the small airways make a difference to Scadding Building, National Heart & Lung Institute, Imperial College London & Royal Brompton Hospital, Dovehouse Street, London, SW3 6LY, UK. the patient and specifically, to asthma control? Tel: +44 (0)207 351 8051; Fax: +44 (0)207 351 8937; 4. If so, do doctors need to treat small airways dysfunction? E-mail: [email protected] In particular the role of small particle aerosols in the manage- Received: February 25, 2014; Accepted: April 01, 2014 ment of patients with asthma will be explored, and as there •There are no financial or other issues that might lead to conflict of interest. 376 http://e-aair.org © Copyright The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease AAIR Small Airways Dysfunction in Asthma this chronic disease in the community. However, despite these less than 15% of patients persist with inhaled therapy in the significant advances, the present day control of disease in pa- course of a year.13 These data highlight that despite current ther- tients with asthma remains rather unsatisfactory. apeutic strategies, there remains a great unmet need in the In an European cross-sectional survey, Demoly and col- management of asthmatic patients with mild, moderate and leagues assessed the levels of patient-reported asthma control severe disease. on the health status of patients and their use of healthcare re- sources (visits to their doctor, emergency room attendance, and Small airways phenotype admission to hospital) over a five year period from 2006 to Asthma is now being recognized as a complex clinical syn- 2010.5 The authors observed that despite ongoing treatment, drome, rather than a specific disease entity, and as an ‘umbrella’ more than 50% of all asthmatic patients were still characterized term encompassing a heterogeneous group of phenotypes and as being not well controlled (54% in 2010, 57% in 2008, and 55% endotypes that may have different treatment responses.14,15 In in 2006). The authors also noted that worsening asthma control light of this understanding, the approach of ‘one treatment to fit was associated with significantly greater healthcare resource all’ may not be appropriate, and there is a move towards person- utilisation in the preceding six months of assessment. Similar alising asthma therapy based on specific phenotypes.16 So, could findings have also been reported in the Asia Pacific region by it be that asthmatic patients who continue to experience poor Lai and colleagues, where daytime asthma symptoms were re- disease control and frequent exacerbations exhibit persistent ported by 51% of asthmatic patients and only 34% of patients airways inflammation that is not being addressed by existing an- with severe persistent asthma felt their disease was well or ti-inflammatory treatments? More specifically, a key contributo- completely controlled.6 Certainly, the compliance of patients ry factor to poor disease control might be that such patients ex- with their prescribed medication and also the correct use of in- press a ‘small airways phenotype’, where there is ongoing and haled respiratory medicines are important concerns and repre- unopposed small airways inflammation and dysfunction that is sent significant factors contributing to reported studies on poor not being targeted or controlled by current therapies; that is, the asthma control.7 The management of patients with asthma has inability of the inhaler devices that are routinely being used in been improved with the advent of combination treatment of in- clinical practice to effectively deliver and deposit their aero- haled corticosteroids (ICS) with long-acting beta-agonist solised medicine to treat the small airway region of the lung.17 (LABA), where combination therapy has clearly been shown Historically, the small airways are defined as airways with an clinically to improve disease control through mechanisms that internal diameter of less than 2 mm.18,19 Weibel’s seminal work modulate the underlying airways inflammation.8,9 Yet studies on the quantitative study of lung anatomy helps us to acknowl- have shown that asthmatic patients are still not optimally con- edge there are three main lung regions to appreciate when con- trolled with such management. sidering airway disease and targeted treatment; the large (>2 In a post hoc analysis of data from the Formoterol and Corti- mm) conducting airway zone which comprises airway genera- costeroid Establishing Therapy (FACET) study,10 O’Byrne and tions 1-7; the small (<2 mm) conducting airway zone, which colleagues reported that the addition of the LABA, formoterol, comprises airway generations 8-16; and the small (<2 mm) re- to the ICS, budesonide, led to a greater probability of well-con- spiratory acinar zone, which comprises airway generations 17- trolled asthma compared to an increased dose of budesonide, 23.20 It is well established that inflammation in asthma involves where treatments were given for one year.11 However, their data the large airways, but histopathological evidence from several showed that nearly 40% of patients on the combination of for- studies have clearly shown that the inflammation in asthmatic moterol 24 µg/budesonide 800 µg daily, did not achieve sus- subjects also involves the small airways; that is, the complete tained well-controlled asthma in the last two months of treat- airway tree.21,22 It is also now recognised that the small airways ment; that is, the patients were characterised as being poorly are the major site of airflow limitation in both asthma and controlled or with intermediate controlled asthma. Indeed, of chronic obstructive pulmonary disease,23,24 yet they are known those patients