Over the past 30 years, pulmonary function testing has come into widespread use. This has been facilitated by several developments:^1,2

1. Miniaturization and advances in computer technology, microprocessor devices have become portable and automated with fewer moving parts.
2. Testing equipment, patient maneuvers, and testing technique have become widely standardized throughout the world through the efforts of professional societies.
3. Widely accepted normative parameters have been established.

Pulmonary function testing is a valuable tool for the evaluation of the respiratory system, representing an important adjunct to the patient history, various lung imaging studies, and invasive testing such as bronchoscopy and open-lung biopsy. The overall approach is to compare the measured values for an individual patient at any particular point in time with normative values derived from population studies. Therefore, the percent predicted normal is used to define normal and abnormal as well as to grade the severity of the abnormality. Practicing clinicians must become familiar with pulmonary function testing because it is frequently used in clinical medicine for evaluation of respiratory symptoms such as dyspnea and cough, for preoperative risk stratification, and for diagnostic purposes for common diseases such as asthma and chronic obstructive pulmonary disease.

Pulmonary function tests (PFTs) is a generic term used to indicate a battery of studies or maneuvers that may be performed using standardized equipment to measure lung function. PFTs may include simple screening spirometry, formal lung volume measurement, diffusing capacity for carbon monoxide, and arterial blood gases. These studies may collectively be referred to as a complete pulmonary function survey.

Before a spirogram can be meaningfully interpreted, one needs to inspect the graphic data (ie, volume-time curve and the flow-volume loop) to ascertain whether the study meets certain well-defined acceptability and reproducibility standards. The interpretative strategy usually involves establishing a pattern of abnormality (obstructive, restrictive, or mixed), grading the severity of the abnormality, and assessing trends over time. A variety of algorithms are available. Automated spirometry systems usually have built-in software that can generate a preliminary interpretation, especially for spirometry; however, algorithms for other pulmonary function studies are not as well established and necessitate appropriate clinical correlation and physician oversight.

Basic concepts of normal pulmonary physiology that are involved in pulmonary function testing include mechanics (airflows and lung volumes), the ventilation-perfusion interrelationship, diffusion/gas exchange, and respiratory muscle or bellows strength. Ventilation is the process of generating the forces necessary to move the appropriate volumes of air from the atmosphere to the alveoli to meet the metabolic needs of the body under a variety of conditions. Simply, the thoracic muscles generate negative pressure in the chest and pleural space, favoring flow of air into the airways and lungs (inspiration). When the pressures equilibrate, the muscles relax and contract, increasing intrathoracic pressure and forcing air out of the lungs (expiration).

With exhalation, the early portion of the maneuver is characterized by high flows, mostly from large airways, and the latter portion is characterized by low flows with a larger contribution from the smaller airways.³ Inspiration is generally not flow limited and is a function of overall muscular effort. In contrast, a variety of factors affect expiratory flow, including the overall driving pressure (which is the pressure head at the alveolus, or P_ALV: the arithmetic sum of pleural pressure, or P_PL; plus pressure from lung elastic recoil, or P_ELAST), airway diameter, overall distensibility of lung and chest wall, dynamic airway collapse (ie, from a flow-limiting segment), and muscular effort. So:

P_ALV = P_PL + P_ELAST

The mechanism for the maximal expiratory airflow limitation seen in normal airways is due to two factors: the gradual pressure drop along the airways as well as dynamic airway compression, with intrathoracic airways downstream becoming narrowed distally to a choke point or equal pressure point. At maximal airflow or during the early part of the expiratory maneuver, the main driving pressure is the intrinsic elastic recoil of the lungs.

Pulmonary function studies use a variety of maneuvers to measure and record the properties of four lung components. These include the airways (both large and small), lung parenchyma (alveoli, interstitium), pulmonary vasculature, and the bellows-pump mechanism. Various diseases can affect each of these components.

Spirometry:

Spirometry is the most commonly used lung function screening study. It generally should be the clinician's first option, with other studies being reserved for specific indications. Most patients can easily perform spirometry when coached by an appropriately trained technician or other health care provider. The test can be administered in the ambulatory setting, physician's office, emergency department, or inpatient setting. The indications for spirometry are diverse (Table 1). It can be used for diagnosing and monitoring respiratory symptoms and disease, for preoperative risk stratification, and as a tool in epidemiologic and other research studies.

Spirometry requires a voluntary maneuver in which a seated patient inhales maximally from tidal respiration to total lung capacity (TLC) and then rapidly exhales to the fullest extent until no further volume is exhaled at residual volume (RV)³ (Figures 1, 2). The maneuver may be performed in a forceful manner to generate a forced vital capacity (FVC) or in a more relaxed manner to generate a slow vital capacity (SVC). In normal individuals, the inspiratory vital capacity, the expiratory SVC, and expiratory FVC are essentially equal. However, in patients with obstructive airways disease, the expiratory SVC is generally higher than the FVC.

A spirometer, including the waterless, rolling seal type, and Stead-Wells water seal type is an instrument that directly measures the volume of air displaced or measures airflow by a flow sensing device, such as a pneumotachometer or a tube containing a fixed resistance to flow (Table 2).² Today, most clinical pulmonary function testing laboratories use a microprocessor-driven pneumotachometer to measure air flow directly and then to mathematically derive volume.

A spirogram is a graphic representation of bulk air movement depicted as a volume-time tracing or as a flow-volume tracing. Values generated from a simple spirogram provide important graphic and numeric data regarding the mechanical properties of the lungs, including airflow (forced expiratory volume in 1 second, or FEV₁, along with other timed volumes) and exhaled lung volume (FVC or SVC). The measurement is typically expressed in liters for volumes or in liters per second for flows and is corrected for body temperature and pressure of gas that is saturated with water vapor. Data from a spirogram provides important clues to help distinguish obstructive pulmonary disorders that typically reduce airflow, such as asthma and emphysema, from restrictive disorders that typically reduce total lung volumes, including pulmonary fibrosis and neuromuscular disease.

A number of spirometry standards have been developed over the years. The American Thoracic Society standardization guidelines for acceptability and reproducibility criteria are shown in Table 3.⁴ A well-trained pulmonary function technician usually coaches the patient through the procedure so that the measurement represents the best possible measure of lung function.

Forced Expiratory Volume In 1 Second
The FEV₁ is the most widely used parameter to measure the mechanical properties of the lungs. FEV₁ accounts for the greatest part of the exhaled volume from a spirometric maneuver and reflects mechanical properties of both the large airways and medium-sized airways. In a normal flow-volume loop, the FEV₁ occurs at about 75% of the FVC. This parameter is reduced in both obstructive and restrictive disorders. In obstructive diseases, FEV₁ is reduced disproportionately to the FVC and is an indicator of flow limitation. In restrictive disorders, the FEV₁, FVC, and total lung volume are all reduced, and in this setting FEV₁ is a measure of volume rather than flow.

Forced Vital Capacity
FVC is a measure of lung volume and is usually reduced in diseases that cause the lungs to be "smaller." Such processes are generally termed restrictive and may include disorders of the lung parenchyma, such as pulmonary fibrosis, or of the bellows, including kyphoscoliosis, neuromuscular disease, and pleural effusion. However, a reduction in FVC is not always due to reduced total volumes and may occur in the setting of "large lungs" hyperinflated due to severe airflow obstruction and air trapping, as in emphysema. In this setting, the FVC is decreased due to reduced airflow, air trapping, and increased residual volume, a phenomenon referred to as pseudorestriction. Reduced FVC may occur despite a normal or increased total lung volume. Therefore, FVC is not a reliable indicator of TLC or restriction, especially in the setting of airflow obstruction. The overall accuracy of the FVC for restriction is about 60%.⁵

Volume-time Tracing and Flow-volume Loop
The volume-time tracing and flow-volume loop ascertain the technical adequacy of a maneuver and therefore the quality of the data (Table 3) as well as identify the anatomic location of airflow obstruction. The volume-time tracing is most useful in assessing whether the end-of-test criteria have been met, whereas the flow-volume loop is most valuable in evaluating the start-of-test criteria. The zero time point on the volume-time tracing has been carefully defined and extrapolated to provide a uniform start point for measurement. It corrects for a possible delayed start that may not actually reflect airflow (Figure 3).

The shape of the flow-volume loop may indicate the location of airflow limitation, such as the large upper airways or smaller distal airways (Figure 4). With common obstructive airflow disorders, such as asthma or emphysema, the disease generally affects the expiratory limb and may reduce the effort-dependent peak expiratory flow as well as subsequent airflows that are effort-independent. The descending limb of the expiratory loop is typically concave. In contrast, several unusual anatomic disorders that narrow the large airways may produce a variety of patterns of truncation or flattening of either one limb of the loop (variable upper airway obstruction) or both limbs of the loop (fixed upper airway obstruction).

Additional Tests
A variety of parameters selectively reflect small airways.⁶ These include measures of flow from a spirogram, such as the maximal midexpiratory flow (MMEF) or forced expiratory flow at 25% to 75% vital capacity (FEF_25-75). The FEF_25-75 is the slope of the spirogram between the 25th and the 75th percentile of an FVC maneuver. The closing volume from a single-breath N₂ test and frequency-dependent dynamic lung compliance also can be used to detect small airway disease. It is believed that small airways dysfunction may precede and exist separately in the setting of a normal FEV₁ and FVC. The hypothesis is that smokers may have isolated small airways dysfunction and that there is an obligatory passage through a "silent period" during which only sensitive tests are impaired. However, there is a greater coefficient of variation for these tests of small airways function. In addition, because these measures are vitally influenced by lung volumes, they cannot be interpreted separately without volume correction. Therefore, in practice, these tests have not been particularly helpful to practicing clinicians, and the American Thoracic Society does not recommend their use for detecting small airways disease.⁶

Bronchoprovocation:

To define whether nonspecific airway hyperreactivity is a mechanism for atypical chest symptoms of unclear etiology, inhalational challenge tests are often used in the pulmonary function laboratory.⁷ Methacholine and histamine are the agents most often used with this procedure, although other agents may also be useful. Methacholine is considered safe, can be used in outpatient clinics, and has no systemic side effects.

When the baseline spirogram is relatively normal, inhalational challenge may be performed by aerosolizing progressive concentrations of methacholine by a dosimeter. This is typically performed as a five-stage procedure with five different concentrations. After each stage, the patient performs a spirometry. When there is a 20% reduction in the FEV₁, the test is terminated and is considered positive for airway hyperreactivity. The provocative dosage level of the inhalational agent required to produce a 20% reduction in the FEV₁ is labeled as PD₂₀. If the drop in FEV₁ is less than 20% after five stages of this procedure, the challenge test is considered negative for the presence of airway hyperreactivity.

Bronchial hyperreactivity, as assessed by this inhalational challenge procedure, is very sensitive for the presence of active or current asthma. A positive test is strongly suggestive of bronchial asthma. However, this test may be falsely positive by a variety of conditions, including chronic obstructive pulmonary disease, parenchymal respiratory disorders, congestive heart failure, recent upper respiratory tract infection, and allergic rhinitis. For practical purposes, a negative inhalational challenge with methacholine or histamine excludes active symptomatic asthma as a cause for the patient's chest symptoms.

Lung Volumes:

Because spirometry is an expiratory maneuver, it measures exhaled volume or vital capacity but does not measure residual volume, functional residual capacity (or the resting lung volume), or TLC. Vital capacity is a simple measure of lung volume that is usually reduced in restrictive disorders; however, vital capacity is only an indirect measure of other lung volumes. Because residual volume is not exhaled through the mouth, it is not measured by a spirometer.

Other pulmonary function methodology is required to formally measure TLC, which is derived from the addition of FRC to inspiratory capacity obtained from spirometry.² FRC is usually measured by a gas dilution technique or body plethysmography. Gas dilution techniques are based on a simple principle, are widely used, and provide a good measurement of all air in the lungs that communicates with the airways. A limitation of this technique is that it does not measure air in "noncommunicating" bullae and, therefore, may underestimate TLC, especially in patients with severe emphysema.

Gas dilution techniques use either closed-circuit helium dilution or open-circuit nitrogen washout. They are based on the inhalation of a known concentration and volume of an inert tracer gas, such as helium, followed by equilibration of 7 to 10 minutes in the closed-circuit helium dilution technique. The final exhaled helium concentration is diluted in proportion to the unknown volume of air in the patient's chest (RV). Usually the patient is connected at the end-tidal position of the spirometer; therefore, the lung volume measured is FRC. In the nitrogen-washout technique, the patient breathes 100% oxygen and all the nitrogen in the lung is "washed out." The exhaled volume and the nitrogen concentration in that volume are measured. The difference in nitrogen volume at the initial concentration and at the final exhaled concentration allows a calculation of intrathoracic volume, usually FRC.

Body plethysmography is an alterative method of measuring lung volume that takes advantage of the principle of Boyle's law, which states that the volume of gas at a constant temperature varies inversely with the pressure applied to it. The primary advantage of body plethysmography is that it can measure the total volume of air in the chest, including gas trapped in bullae. Another advantage is that this test can be performed quickly. Drawbacks include the complexity of the equipment as well as the need for a patient to sit in a small enclosed space. A patient is placed in a sitting position in a closed "body box" with a known volume (Figure 5). From the FRC, the patient pants against a closed shutter to produce changes in the box pressure proportionate to the volume of air in the chest. The volume measured by this technique is referred to as thoracic gas volume (TGV) and represents the lung volume at which the shutter was closed, typically FRC.

Diffusing Capacity:

Understanding gas diffusion through the lungs requires recognition of the basics of the gas exchange interface and of the various forces at work by which oxygen and carbon dioxide move by molecular diffusion. Diffusion is limited by the surface area in which diffusion occurs, capillary blood volume, hemoglobin concentration, and the properties of the lung parenchyma that separate the alveolar gas from the red blood cell with the capillary (Figure 6).²

Because all lung volume is not exchanged, most gas exchange occurs as a function of diffusion independent of bulk flow. The role of ventilation is to reset concentration of the bulk flow of gas with the ambient air and to provide a constant gradient for oxygen and carbon dioxide. As spirometry measures the components of this bulk flow exchange, diffusing capacity measures the forces at work in molecular movement with its concentration gradient from the alveolar surface through to the hemoglobin molecule.⁸ The clinical test diffusing capacity of the lung (DL) most commonly uses carbon monoxide (CO) as the tracer gas for measurement because of its high affinity for binding to the hemoglobin molecule. This property allows a better measurement of pure diffusion, such that the movement of the CO is in essence only dependent on the properties of the diffusion barrier and the amount of hemoglobin. The properties of oxygen and its relatively lower affinity for hemoglobin compared with CO also make it more perfusion dependent; thus, cardiac output may influence actual measurement of oxygen diffusion measurements.⁸

Diffusing capacity for CO (DL_CO) is the measure of CO transfer. In Europe, it is called the transfer factor of CO, which describes the process more accurately. DL_CO is a measure of the interaction of alveolar surface area, alveolar capillary perfusion, the physical properties of the alveolar capillary interface, capillary volume, hemoglobin concentration, and the reaction rate of CO and hemoglobin. After a number of simplifications, the commonly used clinical tests to measure DLCO are based on a ratio between the uptake of CO in mL per minute divided by the average alveolar pressure of CO.⁹ Overall, DL_CO is expressed as the uptake of CO in mL of gas STPD (standard temperature and pressure, dry) per minute and per mm Hg driving pressure of CO. In principle, the total diffusing capacity of the whole lung is the sum of the diffusing capacity of the pulmonary membrane component and the capacity of the pulmonary capillary blood volume.^8,9

All methods for measuring diffusing capacity in clinical practice rely on measuring the rate of CO uptake and estimating CO driving pressure.⁸ The most widely used and standardized technique is referred to as the single-breath breath-holding technique. This technique relies on a subject inhaling a known volume of test gas that usually contains 10% helium, 0.3% CO, 21% oxygen, and the remainder nitrogen. The patient inhales the test gas and holds his or her breath for 10 seconds. Exhalation is then performed to "wash out" mechanical and anatomic dead space. Subsequently, an alveolar sample is collected. DL_CO is calculated from the total volume of the lung, breath-hold time, and the initial and final alveolar concentrations of CO. Alveolar volume is estimated by the helium dilution and the initial alveolar concentration of CO. The driving pressure is assumed to be the initial alveolar pressure of CO.

Hemoglobin concentration is a very important measurement in interpreting reductions in DL_CO. Because the hemoglobin present in the alveolar capillaries serves as a CO sink such that oxygen and CO are removed from dissolved gases, the concentration gradient from alveolar to arterial blood remains relatively constant in favor of dissolved gas flow toward the arterial circulation. In this way, a DL_CO may be decreased when the patient is anemic. Because the level of hemoglobin present in the blood and diffusing capacity are directly related, a correction for anemic patients (DL_COc.) is used to further delineate whether a DL_CO is decreased due to anemia or due to parenchymal or interface limitation. If alveolar volume is low and the patient is anemic, both corrections may be performed and reported as the DLVAc.

A list of conditions associated with abnormal DL_CO is listed in Table 8.⁶ Diseases such as interstitial pulmonary fibrosis or any interstitial lung disease may make the DL_CO abnormal long before spirometry or volume abnormalities are present. Low DL_CO is not only an abnormality of restrictive interstitial lung disease but may also occur in the presence of emphysema. In emphysema, the lung volumes may be normal or hyperinflated; therefore, the DLVA is not useful. Additionally, the loss of alveolar surface area, the pathologic lesion of emphysema, is not proportionate to volume. As such, one can understand that other obstructive entities that predominantly affect the airways can have similar spirometry, but a low DL_CO implies a loss of alveolar surface area consistent with emphysema. Unfortunately, it is not always this simple. Some forms of interstitial lung disease may have components of restrictive physiologies, such as low lung volume and clear evidence of decreased diffusion, but may also have airway flow limitation. Sarcoidosis and Wegener's granulomatosis may have an endobronchial component of airway webs or strictures, limiting flow before overt volume loss and still have enough interstitial granulomatous inflammation to reduce the DL_CO.

On the other end of the spectrum, alveolar hemorrhage or congested capillary beds may actually increase the DL_CO. The presence of trapped hemoglobin in proximity to alveolar gas will absorb CO despite the actual severe limitation of gas exchange and oxygen delivery.

As for spirometry, predicted formulas have been established for DL_CO and DLVA. It is important to note, however, that differences in race have been observed in normal subjects, and a race correction of 7% is allowed for African-American patients.⁶

A detailed discussion of equipment is beyond the scope of this chapter. The American Thoracic Society has gone to great lengths to standardize and publish detailed recommendations regarding spirometry, lung volumes, and diffusing capacity.^4,8 These guidelines include the selection of equipment, important technical considerations for variability, and standardization between laboratories for the maneuver. Table 3 lists the acceptability and reproducibility criteria for an adequate spirogram. Table 4 summarizes equipment quality control as recommended by the American Thoracic Society,⁴ and Table 5 lists the suggested performance standards for an office spirometer.

Studies from a healthy population indicate that parameters of lung function, such as FEV₁ or FVC, are affected most significantly by standing height, age, gender, race, and to a lesser extent, by weight.^11-18 If we assume that lung function has a normal Gaussian distribution, then a wide range of values may be considered normal.¹ Because there is no absolute cut-off point for what is normal in biologic systems, an arbitrary statistical approach is widely used to define the lowest 5% of the population, or abnormal. Over the years, many regression equations have been generated by several investigators using different methodologies to study a variety of population cohorts.^11,13,15 The recommendation is for clinical labs to choose a published reference standard that is most similar to the typical patient population at a given institution as well as the testing methods used. The most commonly used standards include Morris et al, Crapo et al, Knudson et al, and most recently, National Health and Nutrition Examination Survey (NHANES III).^16-18,15 These reference standards are based on a cohort of normal people of similar age, height, and race, with normal being defined as individuals without a history of smoking or disease that may impact lung function.

Many approaches have been developed over the years to determine the normal range of spirometry.⁶ These approaches have included using a fixed percentage of predicted (ie, 75%) and a fixed FEV₁-to-FVC ratio, (ie, >0.70), although both of these approaches have no statistical basis and are not recommended.

The American Thoracic Society recommends using the concept of lower limit of normal by identifying the lowest 5% of a population, or patients that fall outside the limits of 1.64 standard deviations from the mean.⁶ This value may be calculated by multiplying 1.65 times the standard error of estimate (1.65 x SEE). Weight is less important as a predictor of lung function. Obese patients may have abnormal spirometry (ie, decrease in FVC) based on the diaphragm's ability to displace the intra-abdominal fat. Body weight has little impact on intrathoracic volume. Race plays an important role in determining normal lung function, as it has been recognized that individuals of different races for any given height and age have proportionately different lung volumes. Specifically, based on anthropometric differences, the lung function for African-Americans is systematically lower compared with Caucasians.⁶ The American Thoracic Society recommends a 12% correction for African-Americans for FEV₁, FVC, and TLC. The FEV₁-to-FVC ratio in African-Americans may be slightly higher compared with Caucasians. A 7% correction for lower values is recommended for FRC and residual volume. However, race-specific reference standards are preferred. Over time, the NHANES III reference equations will likely become the standard in most pulmonary function testing laboratories around the country.¹⁵ The methodologies and the sample size are most robust for this data set, as well as being representative of the American population.

Spirometry:

In 1991, the American Thoracic Society issued a position statement regarding interpretative strategies, which forms the basis for PFT interpretation in practice.⁶ As previously discussed, spirometry is the most widely used screening test of lung function or pulmonary function studies. It is usually the first test to be performed and interpreted. Supplemental studies may be conducted as needed, such as a formal lung volume measurement, diffusing capacity, methacholine provocation test, or cardiopulmonary exercise studies. Spirometry is usually adequate for preoperative risk assessment and stratification. It is also often adequate for rotated obstructive lung disease, such as emphysema or asthma. However, when a patient's symptoms or clinical history cannot be explained by findings on spirometry or when multiple coexisting processes (ie, dyspnea with both heart and lung disease) are present, then further testing is usually warranted.

In a simplistic way, respiratory disease can be classified as obstructive or restrictive processes. Obstructive disorders, such as emphysema or asthma, are characterized by airflow limitation, have increased lung volumes with air trapping, and have normal or increased compliance (based on pressure volume profile). In contrast, restrictive disorders such as pulmonary fibrosis are characterized by reduced lung volumes and an increase in overall stiffness of the lungs (with reduced compliance) (Figure 7). Table 6 summarizes the common obstructive and restrictive lung diseases. Once the technical adequacy of the spirogram has been established, the next step is to classify whether the study is normal, has an obstructive pattern, a restrictive pattern, or a mixed obstructive/restrictive pattern. Figure 8 summarizes this algorithm. In general, the measured values are compared with the lower limits of normal predicted values from one of the published studies. Airflow obstruction exists, by definition, when the FEV₁-to-FVC ratio is below the lower limits of normal. When this ratio is above the lower limits of normal, obstruction is usually excluded. However, occasionally, early termination or short expiratory time can artifactually reduce FVC and falsely normalize the FEV₁-to-FVC ratio to mask obstruction. Once the presence of airflow obstruction is established, then a typical approach in the laboratory is to administer two puffs of inhaled albuterol and repeat the spirogram after 15 minutes to establish bronchodilator responsiveness. Lack of bronchodilator response certainly does not exclude asthma, and the result needs to be used in the context of a patient's clinical history.

Lung Volumes:

Because the FVC is not a reliable measure of TLC, spirometry can only be suggestive of a restrictive process and, in general, should be followed up by lung volume measurement. The algorithm for lung volume interpretation is shown in Figure 9. When spirometry suggests a restrictive process or when the abnormalities seen on the spirogram do not adequately explain a patient's clinical history, then formal measurements of lung volume are helpful. Table 7 summarizes the American Thoracic Society's criteria for grading the severity of lung function abnormalities. TLC can be particularly helpful when a patient has severe airflow obstruction and has a reduction in FVC. In this case, a normal or increased TLC would exclude an associated restrictive process, and the reduction in FVC would actually be a pseudorestriction.

DL_CO:

Diffusing capacity is a pulmonary function test that is commonly performed to help further characterize abnormalities in spirometry or lung volume measurements. The DL_CO is a test that has greater degrees of variability between laboratories and that it is a study that requires some level of expertise to perform reliably. Several processes can affect diffusing capacity (Table 8). Our proposed approach to the interpretation of diffusing capacity is shown in Figures 10 and 11. If diffusing capacity is reduced proportionately to airflow obstruction (a proportionate reduction in FEV₁ and DL_CO), then this is a pattern typical for emphysema. If the DL_CO is reduced proportionately to a reduction in TLC in the context of restrictive abnormalities, then this would be suggestive of a parenchymal process such as pulmonary fibrosis. If there is an isolated or disproportionate reduction in diffusing capacity along with either normal or fairly well-preserved mechanics, then this would be suggestive of predominantly a pulmonary vascular process such as primary pulmonary hypertension or thromboembolic disease. Note that anemia or carboxyhemoglobinemia (from smoking) could affect the measured DL_CO. The concept of a reduced DL_CO that normalizes after correction for a lung volume measurement is often used to describe an extrathoracic or extraparenchymal disease process such as resection, obesity, or neuromuscular disease.² However, this approach has many limitations.

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