Small Airways Disease: Its Role in Chronic Airflow Obstruction

In their article describing the interpretation of tests of early lung dysfunction, Dosman and Cotton stated "we lack a clear understanding of the sequence of pathologic changes that may occur in the development of COPD". This is actually a gross understatement; not only is the sequence of pathologic abnormalities unclear, but the very abnormalities themselves are disputed. To make matters worse, the definition of chronic obstructive pulmonary disease (COPD) is controversial and this automatically affects the choice of pathologic lesions included under that heading. For example, at one extreme, Snider proposed that COPD be defined as a process characterized by chronic bronchitis, with or without emphysema, that may lead to the development of airflow obstruction, and that the term "obstructive" represents a disorder of function, but not a defining characteristic of either chronic bronchitis or emphysema. In this concept alteration of the structure of the small airways is considered to be a part of emphysematous lung destruction. This definition avoids the question of whether emphysema or small airway alteration is responsible for the abnormalities of airflow seen in cigarette smokers, but there is a great deal of evidence to suggest that this idea is incorrect (see later). On the other hand, Mitchell and colleagues suggested that different degrees of airflow obstruction were associated with different types of pathologic lesions: airway changes were more important in causing mild or early COPD, whereas disabling COPD was due to emphysema. Thurlbeck proposed the unifying hypothesis that smoke-induced disease is multifaceted: all or any of chronic bronchitis, emphysema, or small airway disease can occur and any mixture may be found in any patient (Fig. 1). One potential common factor in all three of these conditions is smoke-induced inflammation, and I propose to develop this theme throughout this manuscript to show that airflow obstruction can be due to either alteration of airway structure by inflammation and fibrosis, or can be produced by inflammation-related destruction of the lung parenchyma leading to emphysema and loss of elastic recoil. The concept of "early" obstructive lung disease was first introduced at the same time as the so-called "sensitive" tests of pulmonary function were being developed. These tests were thought to be able to detect abnormalities in airflow at a time when the forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC) were considered to be within normal limits, and, as discussed later, these abnormalities appeared to correlate with alteration of the structure of the small airways; hence, they are often referred to as "tests of small airways." Again, this concept is confounded by definition: There are two potential meanings of early in regard to pulmonary function tests. The tests could be detecting alterations in the airway structure that would remain stable and would not really produce significant clinical problems. Alternatively, the airway abnormalities could be the initial stages of significant disease, which would progress over a period of time and eventually produce disabling airflow obstruction. Although most investigators have assumed that the latter is true (hence the interest in "early" disease), the former is still a realistic possibility. In this article I consider the issues just listed in detail and examine five general areas: (1) The nature of the data relating cigarette smoke and small airways abnormalities as well as the differ-