Published:
August 1, 2010


Pulmonary Function Testing

Thomas R. Gildea

Kevin McCarthy

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Pulmonary function testing has come into widespread use since the 1970s. This has been facilitated by several developments.1,2 Because of miniaturization and advances in computer technology, microprocessor devices have become portable and automated with fewer moving parts. Testing equipment, patient maneuvers, and testing techniques have become widely standardized throughout the world through the efforts of professional societies. Widely accepted normative parameters have been established.

Definition

Pulmonary function testing is a valuable tool for evaluating 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. Insight into underlying pathophysiology can often be gained by comparing the measured values for pulmonary function tests obtained on a patient at any particular point with normative values derived from population studies. The percentage of predicted normal is used to grade the severity of the abnormality. Practicing clinicians must become familiar with pulmonary function testing because it is often used in clinical medicine for evaluating respiratory symptoms such as dyspnea and cough, for stratifying preoperative risk, and for diagnosing 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 can 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 (the volume-time curve and the flow-volume loop) to ascertain whether the study meets certain well-defined acceptability and reproducibility standards. Tests that fail to meet these standards can provide useful information about minimum levels of lung function, but, in general, they should be interpreted cautiously. The interpretive strategy usually involves establishing a pattern of abnormality (obstructive, restrictive, or mixed), grading the severity of the abnormality, and assessing trends over time. Various 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.

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Physiology

Basic concepts of normal pulmonary physiology that are involved in pulmonary function testing include mechanics (airflows and lung volumes), the ventilation-perfusion interrelationship, diffusion and 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 contraction of the diaphragm and other inspiratory muscles expands the thorax, generating negative pressure in the pleural space. One component of pleural pressure, known as transpulmonary pressure, causes a flow of air into the airways and lungs (inspiration). When the transpulmonary and alveolar pressures equilibrate, airflow stops, the inspiratory muscles relax, and the lungs and chest wall elastic recoil raise pleural pressure, forcing air out of the lungs (expiration).

With a forced exhalation, the early portion of the spirometry 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 Forced 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, airway diameter, overall distensibility of the lungs and chest wall, dynamic airway collapse (from a flow-limiting segment), and muscular effort. The overall driving pressure is the pressure head at the alveolus, or PALV, which is the difference between pleural pressure (PPL) and negative transpulmonary pressure (PTP). So:

PALV = PPL + PTP

The mechanism for the maximal expiratory airflow limitation seen in normal airways results from the gradual drop in pressure inside the conducting airways from the alveoli to the mouth, creating a transmural pressure gradient with the pleural pressure. This can cause dynamic airway compression and narrowing or closure of airways that have lost elastic recoil support from the lung parenchyma.

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Battery of maneuvers

Pulmonary function studies use a variety of maneuvers to measure and record the properties of four lung components. These include the airways (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 (Box 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.

Box 1: Indications for Spirometry
Diagnostic
To evaluate symptoms
  • Chest pain
  • Cough
  • Dyspnea
  • Orthopnea
  • Phlegm production
  • Wheezing
To evaluate signs
  • Chest deformity
  • Cyanosis
  • Diminished breath sounds
  • Expiratory slowing
  • Overinflation
  • Unexplained crackles
To evaluate abnormal laboratory tests
  • Abnormal chest radiographs
  • Hypercapnia
  • Hypoxemia
  • Polycythemia
To measure the effect of disease on pulmonary function
To screen persons at risk for pulmonary diseases
  • Smokers
  • Persons in occupations with exposures to injurious substances
Some routine physical examinations
  • To assess preoperative risk
  • To assess prognosis (lung transplant, etc.)
  • To assess health status before enrollment in strenuous physical activity programs
Monitoring
To assess therapeutic interventions
  • Bronchodilator therapy
  • Steroid treatment for asthma, interstitial lung disease, etc.
  • Management of congestive heart failure
  • Other (antibiotics in cystic fibrosis, etc.)
To describe the course of diseases affecting lung function
  • Pulmonary diseases
  • Obstructive small airway diseases
  • Interstitial lung diseases
  • Cardiac diseases
  • Congestive heart failure
  • Neuromuscular diseases
  • Guillain-Barré syndrome
To monitor persons in occupations with exposure to injurious agents
To monitor for adverse reactions to drugs with known pulmonary toxicity
Evaluation of Disability or Impairment
To assess patients as part of a rehabilitation program
  • Medical
  • Industrial
  • Vocational
To assess risks as part of an insurance evaluation
To assess persons for legal reasons
  • Social Security or other government compensation programs
  • Personal injury lawsuits
  • Other
Public Health
  • Epidemiologic surveys
  • Comparison of health status of populations living in different environments
  • Validation of subjective complaints in occupational or environmental settings
  • Derivation of reference equations

© 2003 The Cleveland Clinic Foundation.


Spirometry requires a voluntary maneuver in which a seated patient inhales maximally from tidal respiration to total lung capacity and then rapidly exhales to the fullest extent until no further volume is exhaled at residual volume3 (Figs. 1 and 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 persons, the inspiratory vital capacity, the expiratory SVC, and expiratory FVC are essentially equal. However, in patients with obstructive small airways disease, the expiratory SVC is generally higher than the FVC. This difference might, however, be due partly to the difficulty in maintaining a maximum expiratory effort for an extended time period without experiencing dizziness or lightheadedness.

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 (Box 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.

Box 2: Types of Spirometers
Volume
  • Bellows
  • Rolling seal
  • Water
  • Dry
Flow Sensing (Pneumotach)
  • Fleisch
  • Screen
  • Hot-wire
  • Turbine

Adapted from Miller WF, Scacci R, Gast LR: Laboratory Evaluation of Pulmonary Function. Philadelphia, JB Lippincott, 1987.


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 [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 provide 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 Box 3.4 A well-trained pulmonary function technician usually coaches the patient through the session until the demonstrated reproducibility of key parameters suggests the results represent the best possible measure of lung function at that time.

Box 3: Acceptability and Reproducibility Criteria for Spirograms
Acceptability Criteria
Free from artifacts
  • Cough or glottis closure during the first second of exhalation
  • Early termination or cutoff
  • Variable effort
  • Leak
  • Obstructed mouthpiece
Good start
  • Extrapolated volume is <5% of FVC or 0.15 L, whichever is greater or
  • Time to PEF is <120 ms (optional until further information is available)
Satisfactory exhalation
  • 6 sec of exhalation and/or a plateau in the volume-time curve or
  • Reasonable duration or a plateau in the volume-time curve or
  • The subject cannot or should not continue to exhale
Repeatability Criteria
After three acceptable spirograms have been obtained, apply the following tests.
  • Are the two largest FVCs within 0.2 L of each other?
  • Are the two largest FEV1s within 0.2 L of each other?
If both of these criteria are met, the test session may be concluded.
If both of these criteria are not met, continue testing until:
  • Both of the criteria are met with analysis of additional acceptable spirograms or
  • A total of eight tests have been performed or
  • Save a minimum of three best maneuvers

Adapted from American Thoracic Society: Single-breath carbon monoxide diffusing capacity (transfer factor). Recommendations for a standard technique—1995 update. Am J Respir Crit Care Med 1995;152:2185-2198.
© 2003 The Cleveland Clinic Foundation.


Forced Expiratory Volume in 1 Second

The FEV1 is the most widely used parameter to measure the mechanical properties of the lungs. In normal persons, the FEV1 accounts for the greatest part of the exhaled volume from a spirometric maneuver and reflects mechanical properties of the large and the medium-sized airways. In a normal flow-volume loop, the FEV1 occurs at about 75% to 85% of the FVC. This parameter is reduced in obstructive and restrictive disorders. In obstructive diseases, FEV1 is reduced disproportionately to the FVC, reducing the FEV1/FVC ratio below the lower limit of normal and indicates airflow limitation. In restrictive disorders, the FEV1, FVC, and total lung capacity are all reduced, and the FEV1/FVC ratio is normal or even elevated.

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 can 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 can 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 can occur despite a normal or increased total lung volume. Therefore, FVC is not a reliable indicator of total lung capacity 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 (see Box 3) as well as identifying 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 technique of back-extrapolation of the start of the test to establish a zero time point on the volume-time tracing has been carefully defined and provides a uniform start point for timed measurements. It corrects for delayed or hesitant starts that might otherwise be mistaken for a falsely reduced FEV1. Standards for acceptability define limits for the degree of hesitation that can still yield an acceptable FEV1 (see Box 3). The loss of elastic recoil characteristic of emphysema results in airflow limitation during the maximal forced exhalation that may be grossly underestimated if the patient applies less than maximal expiratory force. Such efforts may still be deemed acceptable using the criteria of extrapolated volume. The time to peak flow appears to have excellent usefulness in identifying such efforts in this population (time to peak flow will be greater than 120 msec when effort is submaximal), but it is not yet a recommended acceptability criterion (Fig. 3).

The shape of the flow-volume loop can indicate the location of airflow limitation, such as the large upper airways or smaller distal airways (Fig. 4). With common obstructive airflow disorders, such as asthma or emphysema, the disease generally affects the expiratory limb and can reduce the effort-dependent peak expiratory flow as well as subsequent airflows that are independent of effort. The descending limb of the expiratory loop is typically concave. In contrast, several unusual anatomic disorders that narrow the large airways can 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 (FEF25-75). The FEF25-75 is the slope of the spirogram between the 25th and the 75th percentiles of an FVC maneuver. Normal values and lower limits of normal for the FEF25-75% have been published.7 Care must be taken to use the statistically defined lower limit of normal and avoid assessing this parameter using the percentage of predicted normal value because the lower limit of normal falls significantly with age.

The closing volume from a single-breath N2 test and frequency-dependent dynamic lung compliance also can be used to detect small airways disease. It is believed that small airways dysfunction can precede and exist separately in the setting of a normal FEV1 and FVC. The hypothesis is that smokers might 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 Normal values for a new parameter to assess small airways function, the FEV3/FVC ratio, are available, but this parameter has not yet been sufficiently validated.8

Bronchoprovocation

To define whether nonspecific airway hyperreactivity is a mechanism for atypical chest symptoms of unclear origin, inhalational challenge tests are often used in the pulmonary function laboratory.9-11 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 increasing 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 concentration dosage level of the inhalational agent required to produce a 20% reduction in the FEV1 is labeled PC20FEV1. If the drop in FEV1 is less than 20% after five stages of this procedure, the challenge test is considered negative for airway hyperreactivity. A PC20FEV1 of less than 8 mg/mL suggests clinically important 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 strongly suggests bronchial asthma. However, this test may be falsely positive in a variety of conditions, including chronic obstructive pulmonary disease, parenchymal respiratory disorders, congestive heart failure, recent upper respiratory tract infection, and allergic rhinitis. A negative inhalational challenge with methacholine or histamine has been believed to exclude active symptomatic asthma as a cause for the patient's chest symptoms; however, a recent study suggests that significant changes in another measure of airway function, specific airways conductance (SGaw), can occur during a methacholine challenge in the absence of a significant change in FEV1. This study was duplicated in our laboratory with the same results (unpublished).

Lung Volumes

Because spirometry is an expiratory maneuver, it measures exhaled volume or vital capacity but does not measure residual volume, functional residual capacity (resting lung volume), or total lung capacity. Vital capacity is a simple measure of lung volume that is usually reduced in restrictive disorders; however, reduction in the vital capacity measured during spirometry should prompt measurement of lung volumes to confirm the presence or absence of a true restrictive ventilatory disorder.

Other pulmonary function methodology is required to formally measure total lung capacity, which is derived from the addition of functional residual capacity (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 it can underestimate total lung capacity, 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 (residual volume). 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 lungs 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 (Fig. 5). From the FRC, the patient pants with an open glottis 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.

After the FRC is measured by any of these techniques, measurement of lung subdivisions (inspiratory capacity, expiratory reserve volume, vital capacity) ensues, ideally while the patient is still on the mouthpiece. From these volumes and capacities, the residual volume and total lung capacity can be calculated.

Diffusing Capacity

Understanding gas diffusion through the lungs requires recognizing 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 (alveolar-capillary membrane thickness and/or the presence of excess fluid in the alveoli) (Fig. 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.12 The clinical test diffusing capacity of the lung most commonly uses carbon monoxide 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 carbon monoxide in essence only depends 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 carbon monoxide also make it more perfusion dependent; thus, cardiac output can influence actual measurement of oxygen diffusion measurements.12

Diffusing capacity of the lung for carbon monoxide (DLCO) is the measure of carbon monoxide transfer. In Europe, it is often called the transfer factor of carbon monoxide, which describes the process more accurately. DLCO 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 carbon monoxide and hemoglobin. After a number of simplifications, the commonly used clinical tests to measure DLCO are based on a ratio between the uptake of carbon monoxide in milliliters per minute divided by the average alveolar pressure of carbon monoxide.13 Overall, DLCO is expressed as the uptake of carbon monoxide in milliliters of gas at standard temperature and pressure, dry, per minute, and per millimeter of mercury driving pressure of carbon monoxide. 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.12,13

All methods for measuring diffusing capacity in clinical practice rely on measuring the rate of carbon monoxide uptake and estimating carbon monoxide driving pressure.12 The most widely used and standardized technique is the single-breath breath-holding technique. In this technique, a subject inhales a known volume of test gas that usually contains 10% helium, 0.3% carbon monoxide, 21% oxygen, and the remainder nitrogen. The patient inhales the test gas and holds his or her breath for 10 seconds. The patient exhales to wash out a conservative overestimate of mechanical and anatomic dead space. Subsequently, an alveolar sample is collected. DLCO is calculated from the total volume of the lung, breath-hold time, and the initial and final alveolar concentrations of carbon monoxide. The exhaled helium concentration is used to calculate a single-breath estimate of total lung capacity and the initial alveolar concentration of carbon monoxide. The driving pressure is assumed to be the calculated initial alveolar pressure of carbon monoxide. The calculated DLCO is a product of the patient's single-breath estimate of total lung capacity multiplied by the rate of carbon monoxide uptake during the 10-second breath hold.

Hemoglobin concentration is a very important measurement in interpreting reductions in DLCO. Because the hemoglobin present in the alveolar capillaries serves as a carbon monoxide sink such that oxygen and carbon monoxide 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 DLCO 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 (DLCOc) is used to further delineate whether a DLCO is decreased due to anemia or due to parenchymal or interface limitation. Recent work suggests strongly that the practice of dividing the calculated DLCO by the single-breath estimate of total lung capacity (VA) to correct for low lung volumes (the DL/VA ratio) can yield a large number of false-negative results, and this practice should be used cautiously if at all.

A list of conditions associated with abnormal DLCO is listed in Box 4.6 Diseases such as interstitial pulmonary fibrosis or any interstitial lung disease can make the DLCO abnormal long before spirometry or volume abnormalities are present. Low DLCO is not only an abnormality of restrictive interstitial lung disease but also can occur in the presence of emphysema. In emphysema, the lung volumes may be normal or hyperinflated; therefore, the DL/VA is not useful. Additionally, the loss of alveolar surface area, the pathologic lesion of emphysema, is not proportionate to volume. Thus, one can understand that other obstructive entities that predominantly affect the airways can have similar spirometry, but a low DLCO implies a loss of alveolar surface area consistent with emphysema. Unfortunately, it is not always this simple. Some forms of interstitial lung disease can have components of restrictive physiologies, such as low lung volume and clear evidence of decreased diffusion but also can have airway flow limitation. Sarcoidosis and Wegener's granulomatosis can produce an endobronchial component of airway webs or strictures, limiting flow before overt volume loss, and sufficient interstitial granulomatous inflammation to reduce the DLCO.

Box 4: Processes Associated with Alterations in DLCO
Obstructive Lung Diseases
  • Cystic fibrosis
  • Emphysema
Parenchymal Lung Diseases
  • Drug reactions (e.g., amiodarone, bleomycin)
  • Idiopathic
  • Interstitial lung disease
  • Lung disease caused by fibrogenic dusts (e.g., asbestosis)
  • Lung disease caused by biologic dusts (e.g., allergic alveolitis)
  • Sarcoidosis
Pulmonary Involvement in Systemic Diseases
  • Dermatomyositis-polymyositis
  • Inflammatory bowel disease
  • Mixed connective tissue disease
  • Progressive systemic sclerosis
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Wegener's granulomatosis
Cardiovascular Diseases
  • Acute and recurrent pulmonary thromboembolism
  • Acute myocardial infarction
  • Fat embolization
  • Mitral stenosis
  • Primary pulmonary hypertension
  • Pulmonary edema
Other
  • Acute and chronic ethanol ingestion
  • Bronchiolitis obliterans with organizing pneumonia (BOOP)
  • Chronic hemodialysis
  • Chronic renal failure
  • Ciagarette smoking
  • Cocaine freebasing
  • Diseases associated with anemia
  • Marijuana smoking
Increases In DLCO
  • Diseases associated with increased pulmonary blood flow (e.g., left-to-right intracardiac shunts)
  • Diseases associated with polycythemia
  • Exercise
  • Pulmonary hemorrhage
  • DLCO, diffusing capacity of carbon monoxide.

© 2003 The Cleveland Clinic Foundation.


On the other end of the spectrum, alveolar hemorrhage or congested capillary beds can actually increase the DLCO. Hemoglobin trapped in proximity to alveolar gas will absorb carbon monoxide despite the actual severe limitation of gas exchange and oxygen delivery.

As for spirometry, predicted formulas have been established for DLCO and DL/VA. Differences in race have been observed in normal subjects, and a race correction of 7% is allowed for African American patients.6

Exhaled Nitric Oxide

The measurement of exhaled nitric oxide as a reflection of airway inflammation is gaining rapid acceptance as a pulmonary function test. Normal values have been shown to depend on the exhaled flow rate during the measurement. The test is repeated until three reproducible results are obtained. The mean value is reported. Patients are asked to inspire to total lung capacity and then exhale into an analyzer using a steady, controlled exhaled flow rate. The test is rapid and safe and can be performed by most patients. The normal values shown in Table 1 are for a measurement flow rate of 50 mL/sec.14

Table 1: Exhaled Oral Nitric Oxide
Volume (ppb)

Category Adult Child Interpretation
Normal 5-20 5-15 Normal
High normal or increased 20-35 15-25 Moderately raised exhaled nitric oxide can indicate underlying airway inflammation
Colds and influenza can transiently raise exhaled nitric oxide, and some patients have higher baseline exhaled nitric oxide levels than others
Elevated >35 >25
  • Indicates ongoing eosinophilic inflammation
  • Symptomatic patients are likely to respond to steroids
  • Possible causes (if already on steroids) include poor compliance, recent allergen exposure, inadequate steroid dose, and poor steroid response
  • Not all patients with high exhaled nitric oxide levels experience symptoms

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Equipment

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.4,12 These guidelines include the selection of equipment, important technical considerations for variability, and standardization between laboratories for the maneuver. Box 3 lists the acceptability and reproducibility criteria for an adequate spirogram. Table 2 summarizes equipment quality control as recommended by the American Thoracic Society,4 and Box 5 lists the suggested performance standards for an office spirometer.

Table 2: Equipment Quality Control Summary
Test Minimum Interval Action
Volume Daily 3-L syringe check
Leak Daily 3 cm H2O constant pressure for 1 min
Linearity Quarterly
Weekly (flow spirometers)
1-L increments with a calibrating syringe measured over the entire volume range (flow spirometers simulate several different flow ranges)
Time Quarterly Mechanical recorder check with stopwatch
Software New versions Log installation date and perform test using known subject

Adapted from American Thoracic Society: Single-breath carbon monoxide diffusing capacity (transfer factor). Recommendations for a standard technique—1995 update. Am J Respir Crit Care Med 1995;152:2185-2198.
© 2004 The Cleveland Clinic Foundation.


Box 5: Performance Standards for an Office Spirometer
A volume spirometer should:
  • Accumulate volume for greater than 30 sec
  • Accommodate volumes of up to 7 L
  • Be accurate to within 3% or 50 mL of a test volume
A flow-sensing spirometer should:
  • Be able to measure flows up to 12 L/sec
  • Be accurate to within 5% or 0.2 L/sec
Both need:
  • Regular maintenance
  • Routine checks of accuracy of the spirometer and the computer

Adapted from American Thoracic Society: Single-breath carbon monoxide diffusing capacity (transfer factor). Recommendations for a standard technique—1995 update. Am J Respir Crit Care Med 1995;152:2185-2198.


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Normality and predicted equations

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, weight.7,15-21 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 as abnormal. Over the years, many regression equations have been generated by several investigators using different methodologies to study a variety of populations.7,15,17 The recommendation is for clinical laboratories 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 are those of Morris and colleagues,19 Crapo and colleagues,20 Knudson and colleagues,21 and the National Health and Nutrition Examination Survey (NHANES III).7 These reference standards are based on a cohort of normal subjects of similar age, height, and race, with normal being defined as persons without a history of smoking or disease that can affect lung function.

Many approaches have been developed to determine the normal range of spirometry.6 These approaches have included using a fixed percentage of predicted (75%) and a fixed FEV1-to-FVC ratio, (<0.70), 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 1.645 standard deviations from the mean.6 This value may be calculated by multiplying 1.645 times the standard error of estimate (1.645 × SEE).

Weight is less important as a predictor of lung function. Obese patients might have abnormal spirometry (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; it has been recognized that persons 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 whites.6 The American Thoracic Society recommends a 12% correction for African Americans for FEV1, FVC, and total lung capacity. The FEV1-to-FVC ratio in African Americans may be slightly higher compared with whites. 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.7 The methodologies and the sample size are most robust for this dataset, as well as being representative of the American population.

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Clinical interpretive strategies

Spirometry

In 1991, the American Thoracic Society issued a position statement regarding interpretive 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 (e.g., 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) (Fig. 7). Box 6 summarizes the common obstructive and restrictive lung diseases.

Box 6: Common Restrictive and Obstructive Lung Diseases
Common Obstructive Lung Diseases
  • Asthma
  • Asthmatic bronchitis
  • Chronic obstructive bronchitis
  • Chronic obstructive pulmonary disease (includes asthmatic bronchitis, chronic bronchitis, emphysema, and the overlap between them)
  • Cystic fibrosis
  • Emphysema
Common Restrictive Lung Diseases
  • Beryllium disease
  • Congestive heart failure
  • Idiopathic pulmonary fibrosis
  • Infectious inflammation (e.g., histoplasmosis, mycobacterium infection)
  • Interstitial pneumonitis
  • Neuromuscular diseases
  • Sarcoidosis
  • Thoracic deformities

© 2003 The Cleveland Clinic Foundation.


Once the technical adequacy of the spirogram has been established, the next step is to classify whether the study is normal or has an obstructive pattern, a restrictive pattern, or a mixed obstructive and 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 ratio of FEV1 to FVC 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/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 total lung capacity, spirometry can only suggest 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. Box 7 summarizes the American Thoracic Society's criteria for grading the severity of lung function abnormalities. Total lung capacity can be particularly helpful when a patient has severe airflow obstruction and has a reduction in FVC. In this case, a normal or increased total lung capacity excludes an associated restrictive process, and the reduction in FVC is actually a pseudorestriction.

Box 7: Example of Criteria for Assessing the Severity of Abnormalities
Normal
  • The test is interpreted as within normal limits if both the VC and the FEV1/VC ratio are in the normal ranges.
  • Obstructive Abnormality
  • The test is interpreted as showing obstructive abnormality when the FEV1/VC ratio is below the normal range. The severity of the abnormality might be graded as follows:
  • May be a physiologic variant: Predicted FEV1 ≥100%
  • Mild: Predicted FEV1 <100% and ≥70%
  • Moderate: Predicted FEV1 <70% and ≥60%
  • Moderately severe: Predicted FEV1 <60% and ≥50%
  • Severe: Predicted FEV1 <50% and ≥34%
Restrictive Abnormality
  • The test is most reliably interpreted as showing restrictive abnormality on the basis of total lung capacity. If this total lung capacity not available, one may interpret a reduction in the VC without a reduction of the FEV1/VC ratio as a restriction of the volume excursion of the lung. The severity of the abnormality might be graded as follows:
Based on the TLC
  • Mild: Predicted TLC < LLN but ≥70%
  • Moderate: Predicted TLC <70% and ≥60%
  • Moderately severe: Predicted TLC <60%
Based on Spirometry
  • Mild: Predicted VC < LLN but ≥70%
  • Moderate: Predicted VC <70% and ≥60%
  • Moderately severe: Predicted VC <60% and ≥50%
  • Severe: Predicted VC <50% and ≥34%
  • Very severe: Predicted VC <34%

FEV1, forced expiratory volume in 1 second; LLN, lower limit of normal; TLC, total lung capacity; VC, vital capacity.
Adapted from American Thoracic Society: Lung function testing: Selection of reference values and interpretative strategies. Am Rev Respir Dis 1991;144:1202-1218.
© 2003 The Cleveland Clinic Foundation.

Diffusing Capacity of Carbon Monoxide

Diffusing capacity is a pulmonary function test that is commonly performed to help further characterize abnormalities in spirometry or lung volume measurements. The DLCO has greater degrees of variability between laboratories and requires some level of expertise to perform reliably.

Several processes can affect diffusing capacity (see Box 4). Our proposed approach to the interpretation of diffusing capacity is shown in Figures 10 and 11. A pattern of diffusing capacity reduced proportionate to airflow obstruction (a proportionate reduction in FEV1 and DLCO) is typical for emphysema. A DLCO is reduced proportionately to a reduction in total lung capacity in the context of restrictive abnormalities suggests a parenchymal process such as pulmonary fibrosis. An isolated or disproportionate reduction in diffusing capacity along with either normal or fairly well preserved mechanics suggests predominantly a pulmonary vascular process such as primary pulmonary hypertension or thromboembolic disease.

Anemia or carboxyhemoglobinemia (from smoking) could affect the measured DLCO.10 The concept of a reduced DLCO 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, as noted previously, this approach has many limitations.

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Summary

  • Lung function testing helps us to understand the physiologic working of the lungs and chest mechanics.
  • Pulmonary function testing is the primary method used to diagnose, stage, and monitor various pulmonary diseases.
  • Lung function testing requires operators to follow published guidelines for administering and interpreting tests.

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References

  1. In: Clausen JL, Zarins LP (eds): Pulmonary Function Testing, Guidelines and Controversies: Equipment, Methods, and Normal Values. New York: Academic Press, 1982.
  2. Miller WF, Scacci R, Gast LR. Laboratory Evaluation of Pulmonary Function. Philadelphia: JB Lippincott, 1987.
  3. In: Albert RK, Spiro SG, Jett JR (eds): Comprehensive Respiratory Medicine. St Louis: Mosby, 1999, p 43.
  4. Miller MR, Hankinson J, Brusasco V, et al: American Thoracic Society/European Respiratory Society Task Force: Standardization of spirometry. Eur Resp J. 2005, 26: 319-338.
  5. Aaron SD, Dales RE, Cardinal P. How accurate is spirometry at predicting restrictive pulmonary impairment? Chest. 1999, 115: 869-873.
  6. American Thoracic Society. Lung function testing: Selection of reference values and interpretative strategies. Am Rev Respir Dis. 1991, 144: 1202-1218.
  7. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med. 1999, 159: 179-187.
  8. Hansen JE, Sun XG, Wasserman K. Discriminating measures and normal values for expiratory obstruction. Chest. 2006, 129: 369-377.
  9. Crapo RO, Casaburi R, Coates AL, et al: Guidelines for methacholine and exercise challenge testing, 1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med. 2000, 161: 309-329.
  10. Graham BL, Mink JT, Cotton DJ. Effects of increasing carboxyhemoglobin on the single breath carbon monoxide diffusing capacity. Am J Respir Crit Care Med. 2002, 165: 1504-1510.
  11. Parker AL, McCool D. Pulmonary function characteristics of patients with different patterns of methacholine airway hyperresponsiveness. Chest. 2002, 121: 1818-1823.
  12. Crapo RO, Forster RE II. Carbon monoxide diffusing capacity. Clin Chest Med. 1989, 10: 187-198.
  13. American Thoracic Society. Single-breath carbon monoxide diffusing capacity (transfer factor). Recommendations for a standard technique—1995 update. Am J Respir Crit Care Med. 1995, 152: 2185-2198.
  14. R. Dweik, personal communication.
  15. Ghio AJ, Crapo RO, Elliott CG. Reference equations used to predict pulmonary function. Survey at institutions with respiratory disease training programs in the United States and Canada. Chest. 1990, 97: 400-403.
  16. Becklake M, Crapo RO, Buist S, et al: Lung function testing: Selection of reference values and interpretative strategies. Am Rev Respir Dis. 1991, 144: 1202-1218.
  17. Enright PL, Kronmal RA, Higgins M, et al: Spirometry reference values for women and men 65 to 85 years of age. Cardiovascular health study. Am Rev Respir Dis. 1993, 147: 125-133.
  18. Crapo RO, Jensen RL, Hegewald M, Tashkin DP. Arterial blood gas reference values for sea level and an altitude of 1,400 meters. Am J Respir Crit Care Med. 1999, 160: 1525-1531.
  19. Morris AH, Koski A, Johnson LC. Spirometric standards for healthy nonsmoking adults. Am Rev Respir Dis. 1971, 103: 57-67.
  20. Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis. 1981, 123: 659-664.
  21. Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis. 1983, 127: 725-734.

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Suggested Readings

  • American Thoracic Society. Single-breath carbon monoxide diffusing capacity (transfer factor). Recommendations for a standard technique-1995 update. Am J Respir Crit Care Med. 1995, 152: 2185-2198.
  • Becklake M, Crapo RO, Buist S, et al: Lung function testing: Selection of reference values and interpretative strategies. Am Rev Respir Dis. 1991, 144: 1202-1218.
  • Crapo RO, Casaburi R, Coates AL, et al: Guidelines for methacholine and exercise challenge testing, 1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med. 2000, 161: 309-329.
  • Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med. 1999, 159: 179-187.
  • Miller MR, Hankinson J, Brusasco V, et al: American Thoracic Society/European Respiratory Society Task Force: Standardization of spirometry. Eur Resp J. 2005, 26: 319-338.
  • Miller WF, Scacci R, Gast LR. Laboratory Evaluation of Pulmonary Function. Philadelphia: JB Lippincott, 1987.