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. ¹ 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 ² ; 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, ³ 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 V_T: 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. ¹ 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, ¹ more cardiovascular comorbidities, and worse exercise tolerance and dyspnea ⁴ 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. ⁵ 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. ¹ Indeed, some such individuals may benefit clinically from a more proactive approach toward early treatment with BDs. ¹

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, ¹ 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.