Defining Airflow Obstruction: More Data, Further Clarity

Journals do not normally write editorials about letters. Of course, some letters merit attention being drawn to them. When Watson and Crick wrote a letter to Nature in 1953 proposing a new structure for deoxyribose nucleic acid (1), they changed the world and, ultimately, clinical practice. Their letter was really a scientific paper rather than normal correspondence, but research letters can make important contributions to our understanding, which is why this Journal accepts them. A good example of this process is the letter in this issue of the Journal by Neder and colleagues (pp. 760–762), which contributes to the continuing debate about how to interpret the FEV₁/FVC ratio when diagnosing chronic obstructive pulmonary disease (COPD) (2). Before considering their findings, it is worthwhile remembering how this debate began and why it is more important than simple semantics.

Since the 1950s, when the FEV₁/FVC ratio was first described, respiratory physiologists have empirically used a value of 0.7 to define airflow obstruction, as it related well to other more invasive physiological measurements of airflow limitation in patients. This convention was followed when the Global Initiative in Chronic Obstructive Lung Disease incorporated spirometry into their definition of COPD and has remained so since (3).There was a general awareness that the ratio declined with age in apparently healthy people, a point highlighted in a study of older Norwegians (4), which was one of the first to point out the implications of this change for the diagnosis of COPD. Subsequently, the Global Lung Function Initiative developed values for the lower limit of normal (LLN) of the ratio, which meant that many older people with ratios below 0.7 would be considered healthy, and, if symptomatic, their problems would be attributed to other conditions. This distinction is at the heart of this debate about definitions. Proponents of the LLN approach believe that abnormal values are those that fall outside the range seen among healthy people, whereas advocates of the fixed ratio believe that delayed lung emptying is abnormal regardless of the age at which it occurs. Here, the example of hypertension is instructive. When I graduated, a systolic blood pressure of 160 mm Hg in a man of 70 was considered “normal aging,” but treatment intervention studies have shown that clinical outcomes can be improved by bringing systolic pressure down to a more “physiological” range. Hence, definitions have consequences.

Many studies have tried to address this conundrum. Population data have shown that the outcomes for patients with a reduced fixed ratio that was within the LLN (discordant values) were little different from those with a fixed value above 0.7 (5). Post hoc analysis of large populations recruited to a clinical trial because they had symptoms and a fixed ratio below 0.7 found that patients discordant for the diagnosis of COPD using LLN criteria were somewhat more likely to report cardiovascular comorbidity but were as likely as other participants to die during follow up (6). More recently, a study of over 24,000 people found that hospitalization and death were more common in discordant patients than in those with a ratio above the LLN and 0.7, and it identified 0.7 as the fixed value with the best discrimination of outcomes (7).

The data reported by Neder and colleagues add to that approach. Like Bhatt and colleagues (7), they sampled a general population and studied 715 tobacco-exposed people: 323 with normal values by LLN and fixed definitions, 134 with discordant values, and 258 in whom both metrics were abnormal. As expected, the discordant individuals were older, were more likely to be male, and reported more cardiovascular comorbidity than the healthy concordant group. This investigation focused on the differences in lung mechanics and exercise performance between these groups. Table 1 of their paper shows a gradation in the degree of absolute abnormality of FEV₁/FVC across the three groups, which is paralleled by increases in residual volume and falls in Dl_CO. Interestingly, the degree of ventilatory inefficiency and peak work rate were reduced to a similar degree in the discordant and concordant obstructed groups, whereas more patients in each group were limited by breathlessness rather than leg fatigue compared with concordant unobstructed subjects. This helps explain why the discordant obstructed group reported a higher Medical Research Council grade than the unobstructed concordant subjects.

Inevitably, the reader craves more information. It would have been helpful to have quantitative computed tomography data in the discordant patients and more data about the functional impact of the cardiovascular comorbidities. Likewise, data on the exercise performance of those not reporting cardiac problems in each group would have been of interest. Given that these investigators have led the way in our understanding of dynamic hyperinflation in COPD even in those with mild airflow obstruction, data about this variable would be of considerable interest. The letter format makes it impractical to explore the data in such detail, but future investigators should purse these avenues to better characterize what is likely to be a heterogeneous subgroup of people.

The work described in this letter compliments that of large longer studies (7), and together, they suggest that an abnormal fixed ratio does identify people at risk for both physiological and clinical problems. However, the specificity of any of these indices in those on the borderline between health and disease remains uncertain. This has led to a series of investigators analyzing data from COPDGene to propose a new definition of COPD by incorporating computed tomography variables that are abnormal before either the LLN or fixed ratio change (8). How easily this approach translates to the clinical arena remains to be seen (9). As Neder and colleagues suggest, a more holistic approach looking at both physiological and clinical abnormalities when attributing a diagnostic label to people with borderline spirometric abnormality is required. In the future, studies directed to this not inconsiderable subgroup of people are needed to determine whether other interventions, especially pharmacological ones, are of value.