Small-particle Aerosols and Small Airway Involvement in Asthma
Small-particle Aerosols and Small Airway Involvement in Asthma
US Respiratory Care 2005
Published: October 2008
Published: October 2008
Refence Section a report by Donald P Tashkin, MD Professor of Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles Introduction Asthma is the most common chronic lung disease, currently afflicting an estimated 20 million people in the US.1 With a rising prevalence worldwide, it constitutes an increasing cause of morbidity and an enormous burden to the healthcare economy.Asthma is now recognized as a chronic inflammatory disorder of the airways, which is observed at all stages of asthma severity, even in newly diagnosed patients.2
According to international guidelines, the primary goal of asthma treatment is to achieve optimum control of asthma by suppressing airway inflammation, thereby reducing the risk of life- threatening exacerbations and long-term morbidity.2 Inhaled corticosteroids (ICS), the most potent anti- inflammatory agents currently available, are recommended as primary therapy for achieving control of persistent asthma; for patients whose asthma is not adequately controlled with ICS therapy alone, increasing the dose of ICS or the addition of an inhaled long-acting beta-agonist is recommended.2 However, despite maximal therapy with ICS with or without the addition of a long-acting beta-agonist, 20% to 50% of patients with asthma of varying severity fail to achieve good control of their asthma, while 50% to 85% are unable to achieve total control (i.e. no daytime symptoms, nocturnal awakenings, emergency room (ER) visits, or need for rescue beta-agonist use, and normal lung function).3 Several reasons probably account for these discouraging findings. Among these are limitations of current inhaled therapy, which may fail to adequately suppress inflammation at all sites in the lower airway - particularly the peripheral airways,which are increasingly recognized as a major site of pathology in asthma and yet are poorly penetrated by conventional ICS.
Histopathologic Evidence of Small Airway Disease in Asthma The inflammatory changes in asthma have been described most often for the large central airways using the commonly available techniques of endobronchial biopsy and bronchoalveolar lavage.Access to the distal airways via bronchoscopy is restricted,however,because of their small dimensions (?2mm in diameter, corresponding to the eighth generation of the tracheobronchial tree),4 limiting direct ante-mortem evaluation of small airway inflammation in asthma. However, post-mortem analyses from as early as the 1920s indicated that the inflammatory changes in asthma were present diffusely throughout the tracheobronchial tree, extending from the central to the peripheral airways.5 More recently, using morphometric and immuno- histologic techniques, a number of investigators have reported inflammatory changes, and increased wall thickness due to airway wall remodeling,in the peripheral airways of patients with fatal asthma, and those with relatively mild asthma who died from a non-respiratory cause or had undergone lung resection for tumor. For example, Saetta et al.6 found evidence of increased mucus plugging, thickening of the smooth muscle layer and inflammatory infiltration with mononuclear cells and eosinophils in the peripheral aiwrays of patients dying of asthma. Kuwano and colleagues7 noted thickening of the sub-mucosa, smooth muscle area, and adventitia of the small airways in patients with severe fatal asthma, and those with milder non-fatal asthma, and these morphologic changes were more prominent than those noted in patients with COPD undergoing lung resection for tumor. Carroll et al.8 found fixed structural changes indicative of airway wall remodeling in the large and small airways of patients with fatal asthma,but predominantly in the small airways of patients with milder, non-fatal asthma. Hamid et al. noted an influx of T-lymphocytes and eosinophils in all-sized airways of asthmatics undergoing lung resection for carcinoma, but activated, EG2+ eosinophils were more numerous and mRNA for interleukin (IL)-5 and eotaxin was expressed to a greater extent in small than large airways.9,10 Finally, comparing endobronchial biopsies of large airways with transbronchial biopsies (which reflect distal lung, presumably including bronchiolar, tissue), Kraft and co- workers noted more eosinophilic inflammation in the peripheral tissues than large bronchi in the early morning hours, particularly in those with nocturnal asthma.11 Physiologic Evidence of Small Airway Abnormality in Asthma Involvement of the small airways in asthma is also reflected by physiologic studies. Over three decades Small-particle Aerosols and Small Airway Involvement in Asthma Donald P Tashkin, MD, is Professor of Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at the University of California, Los Angeles (UCLA). He has received the Trudeau Society of Los Angeles Lifetime Achievement Award and the American Lung Association of California Gold Medal for the most meritorious service in the campaign against lung disease. He is a Fellow of the American College of Physicians and American College of Chest Physicians. He serves as Guest Editor for several scientific journals, including the American Journal of Respiratory and Critical Care Medicine, the European Respiratory Journal, Chest and the Journal of Allergy and Clinical Immunology, and sits on the editorial boards of Respiratory Medicine and Respiratory Research. His research interests include the pulmonary effects of smoked substance abuse and community air pollution, the pathophysiology, prevention and treatment of chronic obstructive pulmonary disease (COPD), and the pathophysiology and clinical pharmacology of asthma.
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