Body Plethysmography is Helpful for COPD Diagnosis, Determination of Severity, Phenotyping, and Response to Therapy

Measurement of forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) represents the most suitable first-line method to assess lung function in clinical practice (1). In COPD, for instance, spirometry helps identify the presence of airflow obstruction and establish therapy according to the severity of the defect (2). Yet, accumulated evidence suggests that, in several instances, simple spirometry outside the frame of absolute lung volumes is of limited value for diagnosis, phenotyping, grading severity, follow-up and treatment (3, 4). In this editorial we do offer a critical appraisal of what measuring lung volumes may add to spirometry in COPD.

To defend this idea, we will first show that, from a technical point of view, lung volumes measurement is a simple test to do for both technicians and patients, is cheap, can be performed in few minutes and repeated over time, gives very repeatable and reproducible values, and is absolutely safe for the patients. Even though a variety of methods have been developed in the past for the measurement of absolute lung volumes (3), total body plethysmography is the one that endured for the time, thus gaining large popularity and consent. As a matter of fact, since its first (1956) description by Dubois et al. (5), total body plethysmography has hardly changed. The measurement is based on Boyle–Mariotte's law, which states that when a constant mass of gas, under isothermal conditions, is compressed or decompressed in an enclosed space, gas volume and pressure change in a way that their product remains constant. From the relationship between these two variables, lung volume can be estimated (5). The maneuver is performed at the end of tidal expiration and immediately followed by a full lung inflation and a slow expiration, so that functional residual capacity (FRC), total lung capacity (TLC), and residual volume (RV) can be estimated (3).

The methodology is robust and easy to perform in most patients. The overestimation of lung volumes in severe airflow obstruction can be minimized by keeping the panting frequency during the maneuver slightly below 1 Hz (6). We accept that other techniques, such as those based on gas dilution principles, are much less suitable in clinical practice especially in patients with severe lung disease because they are more complicated and time consuming than body plethysmography (3). Yet, this does not detract from the fact that measuring lung volumes by plethysmography is everything but ­difficult or hard to do in patients.

There are several advantages to measure lung volumes in clinical practice. Breathlessness is the predominant symptom at presentation in many obstructive, restrictive and mixed lung diseases (7). Apart from smoking-related lung diseases, chronic cigarette consumption is also an independent risk factor of atherosclerotic cardiovascular disease and heart failure (8). Hence, early partitioning of the relative roles played by lungs and heart as determinants of unexplained dyspnea in a chronic current or former smoker may be a ­daunting task. Measuring lung volumes helps in this respect to rule out any restrictive causes of pulmonary symptoms. If TLC value is normal or near normal, a disproportionate reduction of FEV₁ in relation to the maximal volume that can be displaced from the lung, i.e., an FEV₁/FVC ratio below the lower limit of normal range (LLN), indicates the presence of an obstructive abnormality generally due to bronchial asthma and/or COPD (4). Spirometry may also be of help to examine the bronchomotor response to inhaled b₂-agonist and/or anticholinergic drugs, with an increase in FEV₁ > 400 mL versus baseline being strongly suggestive of the former (9).

Nevertheless, the measurement of absolute lung ­volumes allows identify significant associated pathophysiological abnormalities occurring in the natural history of COPD before any change in spirometry. In the early 1960s, Bates et al. (10) showed that an increased RV may be the earliest functional abnormality in heavy smokers with chronic bronchitis. Subsequent studies, showed that air trapping is likely a combination of tidal expiratory flow-limitation and peripheral airway closure (11, 12). In a 4-yr follow-up study in smokers, Corbin et al. (13) did not find any significant changes in FEV₁ and FEV₁/FVC ratio which remained normal despite an increment in RV and, to a lesser extent, TLC.

The increase of the latter was dependent from a de-crement in lung elastic recoil at high lung volumes, thus allowing FVC and FEV₁ to remain unmodified. On this line of reasoning, recent studies suggest that simple spirometry may be insufficient for a correct diagnosis of COPD. By retrospectively reviewing 1,000 patients with a clinical diagnosis of COPD, Köhler et al. (14) reported that almost 14% had a reduced FEV₁ but an FEV₁/FVC ratio above LLN. This non-specific pattern is generally due to an isolated increase in RV and may occur at any stages of the disease.

In another study, it was documented that the pattern of a reduced FVC and a normal or even slightly increased FEV₁/FVC was consistent with a restrictive abnormality only in 50% of the cases (15). In addition, measuring TLC allows airflow obstruction to be differentiated from restrictive abnormality due to obesity, pleural diseases, chest wall abnormalities, and interstitial lung diseases. It could be argued that lung restriction could also be identified by a low alveolar volume (V_A) measured during single breath lung diffusing capacity for CO (DL_CO). However, the difference between TLC and V_A may be as large as 3-4 liters, especially in airflow obstruction, depending on the severity of the pulmonary defect (16), thus strongly limiting the clinical use of V_A as a surrogate of TLC. Interestingly, in some COPD patients with combined pulmonary fibrosis and emphysema neither spirometry nor lung volumes are significantly abnormal whereas DL_CO is decreased (17). Under these conditions, the effects of reduced lung elastic recoil caused by emphysema are presumably counterbalanced by the increased elastic recoil caused by fibrosis, thus preserving FEV₁ and lung volumes.

Spirometry, used either alone (18) or in combination with clinical data (2), might not be sufficiently sensitive to grade the severity of COPD. There are physiological changes other than FEV₁ that have been found to be more closely related to dyspnea in obstructive lung diseases (19, 20). In particular, FRC is almost invariably increased by static or dynamic mechanisms with increasing severity of airflow obstruction (21). Dynamic lung hyperinflation represents a major burden for patients with severe airflow obstruction and is considered a poor prognostic sign (22). It might be argued that an increase in FRC can be estimated from a specular decrease in inspiratory capacity (IC). However, this is true only if TLC does not change with the disease, which is not necessarily the case in clinical practice. For instance, in the presence of a coexisting restrictive defect, the decrease in IC would indeed, erroneously indicate exaggerated lung hyperinflation, thus leading to an inappropriate increase of the dose of bronchodilator agents.

The opposite is true in case TLC is increased as a result of a decreased lung elastic recoil or chest wall distortion. In a classic 1966 study, Woolcock and Read (23) showed that RV, FRC and TLC values were substantially increased (up to several liters) in asthmatic patients during hospital admissions for acute exacerbations. Most importantly, both absolute lung volumes and breathlessness rapidly decreased (within 1 h) after pharmacological treatment without any changes in FEV₁. Presumably, a decrease in lung elastic recoil due to the development of non-ventilated regions during exacerbations caused the increase in TLC. With the bronchoactive therapy, more lung volume was recruited, thus allowing TLC to decrease and lung recoil to be restored to pre-­exacerbation values. This was associated with a substantial improvement of dyspnoea despite any significant changes in the measured FEV₁.

Recent studies bring further support to the need to combine spirometry to lung volumes in clinical practice in COPD. During the forced expiratory maneuver, alveolar pressure (P_A) increases according to the expiratory effort, absolute lung volume and airflow resistance. As a result, part of the thoracic gas volume is compressed and the FEV₁ measured at the mouth (FEV_1-mo) is smaller than that measured in a total body plethysmograph (FEV_1-pleth) (24). In healthy subjects, the difference between FEV_1-pleth and FEV_1-mo is small (average 4%). However, in obstructive lung diseases this gradually increases with values reaching even 100% or more when airflow resistance becomes high and volume large (24). Because it is the FEV_1-pleth rather than the FEV_1-mo that reflects the mechanical properties of the lungs, it stands to reason that the effects of thoracic gas compression volume (TGCV) have a crucial impact on the evaluation of any interventions on bronchomotor tone or lung volumes and/or severity assessment of the pulmonary defect in COPD patients with predominant emphysema or chronic bronchitis.

By using a volume-displacement body plethysmograph, Sharafkhaneh et al. (25) reported that 23% of the increase in FEV_1-mo after a bronchodilator was the result of a decrease in TGCV. Without this, the increase in the FEV_1-mo would have been significantly smaller. In another study conducted in emphysematous patients after lung volume reduction surgery, the same group reported that about 40% of the increase in FEV_1-mo after the intervention could be explained by the reduction in TGCV rather than true bronchodilation (26). More recently, we examined the changes of FEV_1-pleth and FEV_1-mo after inhaling a bronchodilator agent as a function of lung size in a group of COPD patients known to be significant responders according to current guidelines (27).

The hypothesis was that the bronchodilator responses estimated by the changes in FEV_1-mo are biased by height and gender which are major determinants of absolute lung volume. In contrast to the FEV_1-mo that increased >200 mL and 12% of control in all patients, the FEV_1-pleth remained below the threshold of natural variability in about 50% of the cases. Compared to their counterpart, these subjects had larger lung volumes as a result of height, sex, or predominance of emphysema as part of the disease. In other words, the increase in FEV_1-mo after inhaling a bronchodilator agent is larger in taller than smaller subjects or in males rather than females not because of greater effects of the medication on the bronchomotor tone, as one would assume from the spirometric changes, but simply because of anthropometric differences between subjects (27).

In another recent study conducted in COPD patients with a variable range of emphysema, we reported that, as opposed to the FEV_1-mo that was significantly and remarkably less in emphysema than chronic bronchitis, the FEV_1-pleth, respiratory impedance at 5 Hz measured with the forced oscillation technique, arterial blood gases, physical performance, symptom scores, and exa-cerbation rate were not significantly different between the two groups (28). Grading the severity of the disease by using FEV_1-pleth instead of FEV_1-mo led to remarkable and significant shifts toward less severe classes in patients with prevalent emphysema than in patients with predominant chronic bronchitis. These findings are clinically relevant inasmuch as COPD patients with predominant emphysema may be unnecessarily overtreated with bronchoactive medications simply because of the large effects of TGCV on the FEV₁.

In conclusion, we concur that spirometric measurement of FEV₁ and FVC is simple, well standardized, available in almost every setting, and very useful to assess lung function in COPD. Yet, accumulated evidence suggests that spirometry alone can miss several important functional features in lung disease because of the many complexities of the respiratory system. Among the tests that contribute to identify the presence of airflow obstruction, disease phenotyping, grade severity, and establish therapy, body plethysmography appears to play a crucial role both in clinical practice and research.

Declaration of Interest Statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.