Absence of airflow obstruction on spirometry: can it still be COPD?

BACKGROUND

An FEV1/FVC ratio < 0.7 has been widely used to define airflow obstruction, because, on average, it correlates well with more sophisticated measurements of expiratory flow limitation. In fact, the cut-off point of 0.7 is at the core of the definition of COPD according to the GOLD. It follows that most physicians assume that a post-bronchodilator (BD) FEV1/FVC ratio ≥ 0.7 effectively rules out COPD.

OVERVIEW

A 59-year-old, heavy former smoker (45 pack-years) woman who had complaints of exertional dyspnea (mMRC = 3) received a provisional diagnosis of COPD. Although there was partial improvement with the use of inhaled formoterol (mMRC = 2), she was referred to the pulmonology department for reassessment of diagnosis since her post-BD FEV1/FVC ratio had always been ≥ 0.7 (Figure 1A). Additional lung function tests, however, showed mild gas trapping (↑RV) and moderately ↓DLCO (Figure 1B). Considering that the exertional symptoms of the patient could be a mere reflection of severe deconditioning, a cardiopulmonary exercise test was performed to determine whether there was any evidence that “the lungs” could have explained her breathlessness. As shown in Figure 1C, this was indeed the case: a) dyspnea scores, either as a function of work rate or minute ventilation (⩒E), were typically above the upper limit of normal ; b) there was evidence of critical constraints to tidal volume expansion (Figure 1C, arrow) as tidal volume prematurely reached ≈70% of the inspiratory capacity and ≈0.5 L of inspiratory reserve volume, that is, the end-inspiratory lung volume was too close to TLC, and peak ⩒E approached the estimated maximal voluntary ventilation. Moreover, a chest CT showed emphysema and thickened bronchial walls (Figure 1D).

Figure 1

Physiological and structural investigations in a 59-year-old, former heavy smoker woman with complaints of chronic dyspnea. There was a proportional reduction in FEV1 and FVC, leading to a preserved pre- and post-bronchodilator FEV1/FVC ratio (in A), increased RV and reduced DLCO (in B), mechanical ventilatory limitation to exercise (in C; see text for further elaboration), and emphysema plus thickened airway walls on a chest CT (in D) that jointly indicate the presence of COPD. BD: bronchodilator; FRC: functional residual capacity; eMVV: estimated maximal voluntary ventilation; ⩒E: minute ventilation; ⩒O2: oxygen uptake; and VT: tidal volume.

Although there is ongoing controversy regarding the best cut-off point to define airflow obstruction (a fixed FEV1/FVC ratio < 0.7 or age- and sex-based lower limit of normal), a reduced FEV1/FVC ratio has been considered an indispensable criterion for the diagnosis of COPD. There is mounting evidence that subjects showing intermediate FEV1/FVC ratios (i.e., greater than the lower limit of normal but smaller than 0.7) have higher hospitalization and death rates, more cardiovascular comorbidities, and worse exercise tolerance and dyspnea than do subjects with no obstruction using both criteria. Occasionally, however, FVC decreases roughly in tandem with FEV1 as RV increases despite a preserved TLC, reflecting increased small airway collapse/closure at low lung volumes during the forced maneuver. In fact, a sizeable number of symptomatic smokers with no spirometric evidence of obstruction may show gas trapping and/or ↓DLCO plus structural changes in keeping with COPD. Indeed, some such individuals may benefit clinically from a more proactive approach toward early treatment with BDs.

CLINICAL MESSAGE

The key pathophysiological characteristic of the current definition of COPD (a persistently ↓FEV1/FVC ratio) is not sine qua non in smokers showing gas trapping and/or ↓DLCO and/or emphysema on CT. As such, there is a surge of interest in adding CT variables to the definition of COPD, although we strongly believe that the abovementioned physiological variables should also be taken into consideration. The bottom line is that the diagnosis of COPD in subjects with a high pre-test probability of the disease but a preserved FEV1/FVC ratio requires a more holistic approach, involving assessment of clinical (dyspnea), physiological (lung volumes and DLCO), and anatomical (emphysema) abnormalities.