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Pulmonary Function Testing for Pathologists
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Pulmonary Function Testing for Pathologists Imre Noth, MD
Lung Volumes 15 Tools to Measure Volumes 16 Interpretation of Lung Volumes 17 Flows 17 Airway Resistance 17 Respiratory Muscle Strength 17 Diffusion Capacity 18 Summary 19 References 19
As the name implies, pulmonary function testing provides quantification of pulmonary physiologic function. By definition this information is disease independent and static, representing a point in time evaluation. Nonetheless, this information can be very helpful for building a differential diagnosis. In fact, many pulmonary diseases are clinical syndromes and without either a definitive molecular marker for disease or without unique defining functional features. These diseases therefore often require integration of histopathology with radiologic patterns, clinical context, and functional status. Pulmonary function tests (PFTs) often provide the first diagnostic tool that helps guide a clinical pulmonologist in creating a filing system for a possible differential. This chapter will focus on the basic elements that comprise a full set of PFTs. In general, these consist of lung volumes (TLC, FRC, RV; see Table 2.1 for a list of abbreviations used in this chapter), lung flows by spirometry (FVC, FEV1, FEF25-75), airway resistance (Raw), and capillary bed assessment (DLCO). Correct interpretation of PFTs requires that the patient obtained values be read in comparison with appropriate reference values, resulting in a reporting method of “percent of predicted.” Numerous regression equations have been proposed, and used, all commonly adjust for age, gender, height, and race.1-3 The European Respiratory Society and the American Thoracic Society have published guidelines regarding the conduct of measuring and interpreting PFTs.1,4-6 Furthermore, PFTs provide quantification of the severity of the lung impairment and can be used to evaluate for change in lung function
over time. This change over time in function may be age related or represents deterioration related to a disease state or, potentially, improvement related to institution of therapy. The approach of this chapter is therefore to outline how the functional data from PFTs can help guide that differential. Fundamentally, lung physiologic function will be normal, restrictive, or obstructive. Restriction implies reduction in lung volumes—size of the lungs. Obstructive implies reduced air flows, mostly secondary to narrowing of the airways, such as in asthma,7 or reduced elastic recoil, such as from emphysema,8 leading to greater exhalation times. We will start with simple categorization of normal compared with restrictive and obstructive patterns. Although patterns may be mixed, for purposes of organization, one must be predominant. In truth, many techniques and a plethora of available equipment make this arena very diverse. Therefore each part has pros and cons and must be considered in the interpretation of PFTs. After all the parts are established, pattern recognition is a key element, as with many composite tests in medicine. This chapter seeks to provide a clear understanding of the fundamentals of PFTs. Basic interpretation should allow the pathologist to independently provide additional functional context to their differentials on evaluation of histopathology of lung tissue to better inform the clinician for a diagnosis.
Lung Volumes The first objective of a full set of PFTs involves determination of the size of the lungs or the lung volumes. Almost all pulmonary diseases that affect function can be divided into three simple categories. Obstructive lung diseases will all eventually lead to increased lung volumes. This is because ultimately air gets in but cannot get back out. This effect can result in static air trapping, such as in emphysema, or dynamic air trapping, as in reversible airway disease like asthma.9 Restrictive lung diseases will all lead to some measure of reduction in lung volumes because the lung themselves are stiffer3 or the chest wall either will not allow for expansion (i.e., chest wall restriction) or cannot expand fully (i.e., neuromuscular weakness10). Normal lung size implies no clinical deficit from obstruction or restriction. This leaves the pulmonary vasculature or, alternatively, causes external to the lung as potentially causal for any presenting symptomatology. 15
Practical Pulmonary Pathology The lung volumes and lung capacities refer to volumes associated with different phases of the respiratory cycle. Although the volumes can be directly measured, the available capacities are inferred from the lung volumes. There are a number of volumes that can be measured (Table 2.1 and Fig. 2.1); however, three measures (TLC, FRC, RV) are key in determining restriction versus obstruction. The remaining volumes and capacities represent measures for compartmentalization of the respiratory cycle functions (IRV, TV, ERV, RV, IC, and VC).
Tools to Measure Volumes There are several methodologies to attaining lung volumes. The “gold standard” involves body box plethysmography.2 This method uses Boyle’s
law (PV = nRT) to measure changes in pressure to determine lung volumes assuming the temperature is constant. It is important to note that this measure is ideally conducted with the patient breathing normally and therefore measures the functional residual capacity (FRC). Determination of the total lung capacity and residual volume are therefore determined by simple algebraic addition of inspiratory capacity (FRC + IC = TLC) and subtraction of the vital capacity (TLC − VC = RV). Therefore these last two volumes should be interpreted in light of the quality of the IC and VC. Although this approach is the most accurate, it also involves the largest and most expensive piece of equipment. Therefore many labs will use a closed-circuit technique with a helium dilution or nitrogen washout technique. These techniques make assumptions regarding the equilibration of gas concentrations in the portions
Table 2.1 Common Pulmonary Function Test Terminology TLC = RV + VC = FRC + IC
TLC
Total lung capacity
The volume in the lungs at maximal inflation
FRC
Functional residual capacity
The volume in the lungs at end expiration
RV
Residual volume
The volume that remains after full exhalation
ERV
Expiratory reserve volume
The volume that remains after normal tidal respiratory exhalation above the RV
IRV
Inspiratory reserve volume
The maximal additional inhalable volume starting after a normal tidal volume
IRV = IC − TV
IC
Inspiratory capacity
The maximal volume for inhalation starting at FRC
IC = TV + IRV
IVC
Inspiratory vital capacity
VC
Vital capacity
The total available volume from RV to TLC
TLC − RV = VC
TV
Tidal volume
The normal respiratory cycle volume
FVC
Forced vital capacity
Maximal volume attained on dynamic forced expiration beginning at TLC
FEV1
Forced expiratory volume
Maximal volume attained on forced exhalation in first second
in first second FEV1/FVC
the ratio of the % predicted
Reveals if increased or decreased flows
NIF
Negative inspiratory force
Reveals force generated on inspiration
PEF
Positive expiratory force
Reveals force generated on expiration
DLCO
Diffusion capacity of carbon monoxide
Measures the uptake of CO as surrogate for capillary beds
TLC
Volume Compliance of chest wall
TV FRC ERV Compliance of lung RV
Pressure
Normal
Figure 2.1 The volumes of the lung are determined by the pressure-volume relationship between the chest wall, which exerts negative force on the intrathoracic shape as the ribs are built like a “bow” of a bow and arrow set, and the lung, which, like a balloon, has elastic recoil that exerts a positive force to keep it small. The neutral point is presented by the balance of these forces at the functional residual capacity (FRC) and where we spend the majority of our time when not actively inhaling or exhaling. ERV, Expiratory reserve volume; RV, residual volume; TLC, total lung capacity, TV, tidal volume. 16
Pulmonary Function Testing for Pathologists of the lung that communicate with the breathing circuit.2 The key limitation of these last two approaches is that areas of the lung that involve trapped air (bullous disease in example) do not necessarily communicate with the breathing circuit and therefore result in an underestimation of the total volume.
Interpretation of Lung Volumes The average TLC will be approximately 6 L11; however, it is critical to recognize that these volumes are dependent on the height, age, gender, and race of the patient.2 A person only 5 ft tall will obviously have much smaller lungs than another individual more than 6 feet tall. Therefore all lung function testing is adjusted for these variables using various regression equations from known populations to normalize values to a percent of predicted, with 100% representing the ideal normal. Because of the high degree of variability of what constitutes “normal,” most interpreters consider the confidence interval of normal and ±20%. Therefore normal volumes range from 80% to 120% of predicted. Thus, by definition, pulmonary function testing commonly ruled as “obstructive” would have lung volumes that are elevated beyond 120% of predicted. This is where pattern recognition comes into play. Although elevation in TLC is used for the primary interpretation, elevation in all three key lung volumes is expected in classic obstructive lung disease, such as emphysema and chronic bronchitis. There are three basic restrictive patterns. The first is a disproportionate reduction in the FRC (i.e., 60% of predicted) greater than either the TLC (80% of predicted) or RV (80% of predicted). This pattern suggests a chest wall involvement, such as an obesity restriction.12 Most methods, which are outlined in subsequent text, actually measure the volume at FRC. This is because the FRC is the normal resting state, whereas measuring at TLC or RV would be very uncomfortable on the patient. As the TLC and RV are algebraically derived from the FRC, this pattern represents a shift in the resting relationship between the chest wall and the lung compliance (Fig. 2.2). The patient is able to overcome the decrease in FRC from the increased weight on the chest with normal respiratory muscle strength to help partially normalize the latter two values (TLC and RV). The second pattern involves a reduced TLC (80% of predicted), normal FRC (100% of predicted), and increased RV (120% of predicted).10,13 This pattern suggests weakness or poor effort. Again, because the actual number derived is the FRC, the failure to reach TLC on inspiration or RV on expiration while maintaining a normal FRC and therefore chest wall and lung compliance relationship leads to a differential diagnosis of weakness or poor effort (failure to sufficiently perform the test). The third pattern involves equal reduction in all volumes (TLC, FRC, and RV all at 60% of predicted).3 This pattern suggests an intrinsic problem with the lung parenchyma or fibrosis of some kind. The fibrosis leads to increased elastic recoil that causes the lung compliance curve to shift from stiffness, shrinking the size of the lung. Recognition of these patterns helps to outline a differential for the pathologist.
Flows The vast majority of testing will involve spirometry and often spirometry only. Basically, the spirometry measures flow or how good air leaves the lung. Furthermore, as a measure of rate, the flow over time determines the volume.1 Spirometry provides the origin of PFTs. This active dynamic maneuver provides insights into the size of the lungs in the FVC and the obstructive or restrictive nature. These are best revealed by the flow volume loops. Understanding the origins is a fundamental step. The original bell spirometer consists of an upside-down drum spinning on an axle in a
tub of water (Fig. 2.2A). The patient then blows through a hose, which goes into the water and the drum so that when air is blown in, the drum rises on exhalation and falls in inspiration. As the drum spins, a pen can then draw the rise and fall over time on a paper wrapped around the drum. This change in volume over time is a flow rate. It is therefore important to remember that these are not total volumes but flows as they relate to the breathing cycle. With that in mind, spirometry provides several important measures. The patient starts the cycle from the neutral resting position of the FRC (Fig. 2.2B). The first step is inhaling fully to TLC. This provides the IC. Then the patient is instructed to exhale fully for as long and as hard as he or she can. Once the volume plateaus, this provides the FVC. By definition this number is effort dependent, in that a minimum time of exhalation is required. The ATS standard is a minimum of 6 seconds, and some have advocated for an FVC6 as a standard instead of the FVC (Fig. 2.2C).1,14,15 As with all pulmonary function testing, these values are also adjusted for age, gender, and race and normalized to a percent of predicted value. However, the flows should always be taken in context in relationship to the volumes. For example, a patient with a pneumonectomy should not be expected to attain the same flow as one without. Therefore the number may be reduced and not necessarily from restriction or obstruction. The FEV1 is the portion of the curve on exhalation attained in the first second (Fig. 2.3). A little counterintuitively, this number is effort independent. Although the patient needs to blow as hard as he or she can, the amount that comes out is dependent on two factors, both of which are intrinsic to the lung. The first is lung compliance or elastic recoil. In other words, how elastic is the lung? Imagine a balloon being released. The maximal flow is the initial portion and dependent on the stretch on the balloon and not any external compression (i.e., chest wall squeeze). The second is the diameter of the opening of the balloon, or in the case of the lungs, the airways. If the airways are constricted, then the flow rate will be reduced. Therefore the FEV1 is informative regarding the level of obstruction, particularly when we evaluate the FEV1 over the FVC to reveal the elastic recoil of the lung. But the example of the pneumonectomy patient still applies for the FEV1 as well, and the results must be taken in context. Briefly the FEF25–75 assesses the middle part of the curve on the exhalation and provides insights into the mid and small airways disease. Perhaps the most valuable part of the spirometry is the loop itself. The inspiratory limb provides the IC, and then the dynamic single exhalation maneuver provides the FEV1 and FVC together. Therefore if the loop is concave, the flow rate tapers off sharply, indicating obstruction. If the loop is convex, then a greater proportion of the flow than expected is attained more rapidly, suggesting increased elastic recoil and restriction. Modern spirometry uses a pneumotach device, which usually uses a change in pressure to measure airflow rates, allowing for much smaller devices.16
2
Airway Resistance This can be measured similarly to the body box maneuver. The Raw is a linear regression equation using the change in resistance with changing flows. It reflects the large central airways and is most useful as additional information for an obstructive lung disease process.
Respiratory Muscle Strength Two simple maneuvers are conducted in evaluation of respiratory muscles.13 The negative inspiratory force (NIF) measures the pressure generated by patient on inhalation against a closed system. The positive expiratory force (PEF) accomplishes the same but on exhalation. These 17
Practical Pulmonary Pathology Forced expiratory vital capacity maneuver
Patient inspires maximally to total lung capacity, then exhales into spirometer as forcefully, as rapidly, and as completely as possible
A
Vital capacity
Tidal volume
Functional residual capacity
Total lung capacity
Expiratory reserve volume
Residual volume
B 7
Normal
Liters (BTPS)
6 5
Restricted
4 3
Obstructed
2 1 0
C
0
1
2
3
4
5
6
Seconds
Figure 2.2 (A) Demonstration of a classic bell spirometer. (B) The tracing on the “spinning” drum of a bell spirometer, using flow over time, yields the various volumes and demonstrates where and how the algebraic additions give the total volumes. (C) The flow in liters versus time in seconds demonstrates the differences between normal and the reduced states of restricted or obstructed disease. A greater proportion exits within the first second for restriction and smaller proportion for obstructive diseases.
values are very effort dependent and, although predictions are used for normal, which range from 60 to 120 cm H2O, the important values are when these are very low. Concerns are often raised when these numbers fall below 40 because it is not until these low and lower values that an impact is reflected in the FVC. 18
Diffusion Capacity The blood freely and rapidly takes up carbon monoxide (CO).17 Therefore when a patient is asked to inhale a concentration of CO, the amount exhaled will reveal the level of uptake by the blood flow in the lung.
Pulmonary Function Testing for Pathologists
V (L/s)
Exp.
Insp.
Obstructed
7 6 5 4 3 2 1 0 1 2 3 4 5 6 100
0 100
Normal
0 100
Restricted
2
0
Vital capacity (%) Figure 2.3 Flow volume loops. The obstructed pattern demonstrates concavity of the expiratory (top portion) limb of the maneuver, whereas the restricted pattern is more convex. Both reveal a lower expiratory flow rate and total volume than expected in the normal loop. Left, obstructive pulmonary disease; center, normal; right, restricted pulmonary disease; Exp., Expiratory; Insp., inspiratory.
This functions as surrogate for how well the lung exchanges gases. The critical element of that blood flow is represented by the capillary bed. So, although there are a number of eclectic reasons for a decreased DLCO, the primary parenchymal concern is a “loss of capillary beds,” most commonly through alveolar destruction, but also through replacement by a fibrotic process. Alternatives include anemia because the amount of total hemoglobin in the blood cells is what determines the uptake of the CO. Similarly, acute congestive heart failure will lead to spillage of hemoglobin into the alveolar spaces and elevate the uptake of CO, at least transiently with acute pulmonary edema, and restriction from chronic congestive heart failure is possible over time.18 Representative examples of obstructive lung diseases include asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis,19 and restrictive lung diseases include interstitial pneumonitis (UIP, NSIP RB-ILD, DIP) and occupational lung diseases (silicosis, asbestosis, coal worker’s pneumoconiosis). You will notice that a few entities will afflict both the parenchyma and airways, leading to mixed restrictive and obstructive patterns. These include sarcoidosis, hypersensitivity pneumonitis, lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell histiocytosis (PLCH), constrictive bronchiolitis, and combined COPD and ILD.
Summary Pulmonary function testing is a simple and available test that is used in the diagnosis and monitoring of restrictive and obstructive lung diseases. Restrictive lung diseases consist of reduced lung volumes with preserved or increased flows. Obstructive lung diseases consist of increased lung volumes with reduced flows. Measurement of diffusion capacity may enhance the diagnostic and prognostic efficacy of simple spirometry. Although PFTs aid in differentiating the physiologic nature of the disease, they remain nonspecific. Integration of radiologic, histopathologic, and clinical signs and symptoms are required for a definitive diagnosis. References 1. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-338. doi:10.1183/09031936.05.00034805.
2. Wanger J, Clausen JL, Coates A, et al. Standardisation of the measurement of lung volumes. Eur Respir J. 2005;26(3):511-522. doi:10.1183/09031936.05.00035005. 3. Kanengiser LC, Rapoport DM, Epstein H, Goldring RM. Volume adjustment of mechanics and diffusion in interstitial lung disease. Lack of clinical relevance. Chest. 1989;96(5):1036-1042. 4. American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis. 1991;144(5):1202-1218. doi:10.1164/ajrccm/144.5.1202. 5. Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26(5):948-968. doi:10.1183/09031936.05.00035205. 6. Miller MR, Crapo R, Hankinson J, et al. General considerations for lung function testing. Eur Respir J. 2005;26(1):153-161. doi:10.1183/09031936.05.00034505. 7. Gilbert R, Auchincloss JH Jr. The interpretation of the spirogram. How accurate is it for “obstruction”? Arch Intern Med. 1985;145(9):1635-1639. 8. Govaerts E, Demedts M, Van de Woestijne KP. Total respiratory impedance and early emphysema. Eur Respir J. 1993;6(8):1181-1185. 9. Mishima M. Physiological differences and similarities in asthma and copd-based on respiratory function testing. Allergol Int. 2009;58(3):333-340. doi:10.2332/allergolint.09-RAI-0131. 10. Saunders NA, Rigg JR, Pengelly LD, Campbell EJ. Effect of curare on maximum static PV relationships of the respiratory system. J Appl Physiol Respir Environ Exerc Physiol. 1978;44(4): 589-595. 11. Sorensen JB, Morris AH, Crapo RO, Gardner RM. Selection of the best spirometric values for interpretation. Am Rev Respir Dis. 1980;122(5):802-805. doi:10.1164/arrd.1980.122.5.802. 12. Chiang ST, Lee PY, Liu SY. Pulmonary function in a typical case of Pickwickian syndrome. Respiration. 1980;39(2):105-113. 13. Enright PL, Kronmal RA, Manolio TA, Schenker MB, Hyatt RE. Respiratory muscle strength in the elderly. Correlates and reference values. Cardiovascular Health Study Research Group. Am J Respir Crit Care Med. 1994;149(2 Pt 1):430-438. doi:10.1164/ajrccm.149.2.8306041. 14. Redlich CA, Tarlo SM, Hankinson JL, et al. Official American Thoracic Society technical standards: spirometry in the occupational setting. Am J Respir Crit Care Med. 2014;189(8):983-993. doi:10.1164/rccm.201402-0337ST. 15. Akpinar-Elci M, Fedan KB, Enright PL. FEV6 as a surrogate for FVC in detecting airways obstruction and restriction in the workplace. Eur Respir J. 2006;27(2):374-377. doi:10.118 3/09031936.06.00081305. 16. Jenkins SC, Barnes NC, Moxham J. Evaluation of a hand-held spirometer, the Respiradyne, for the measurement of forced expiratory volume in the first second (FEV1), forced vital capacity (FVC) and peak expiratory flow rate (PEFR). Br J Dis Chest. 1988;82(1):70-75. 17. Hughes JM, Pride NB. Examination of the carbon monoxide diffusing capacity (DL(CO)) in relation to its KCO and VA components. Am J Respir Crit Care Med. 2012;186(2):132-139. doi:10.1164/rccm.201112-2160CI. 18. Minasian AG, van den Elshout FJ, Dekhuijzen PN, et al. Pulmonary function impairment in patients with chronic heart failure: lower limit of normal versus conventional cutoff values. Heart Lung. 2014;43(4):311-316. doi:10.1016/j.hrtlng.2014.03.011. 19. Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011;155(3):179-191. doi:10.7326/0003-4819-155-3-201108020-00008.
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Pulmonary Function Testing for Pathologists
Multiple Choice Questions 1. Which of the following procedures is/are used in modern pulmonary medicine to obtain tissue specimens from the lungs? A. Bronchoscopy B. Video-assisted thoracoscopy C. Fine-needle aspiration D. Surgical wedge biopsy E. All of the above ANSWER: E 2. Which ONE of the following statements is FALSE? A. Procurement of clinical and radiologic information is diagnostically more helpful in neoplastic lung disease, compared with nonneoplastic disorders. B. Specimen size and quality affect the level of diagnostic certainty. C. Descriptive diagnoses are acceptable in lung pathology. D. Fine-needle aspiration biopsy of the lung has acceptable specificity and sensitivity compared with diagnosis of pulmonary neoplasms. E. The marginal quality of any given lung biopsy specimen can be described in the surgical pathology report. ANSWER: A 3. Which ONE of the following statements is TRUE? A. Flexible bronchoscopy began in the United States in the late 1980s. B. Rigid bronchoscopy is no longer performed in Asia. C. Flexible bronchoscopy requires general anesthesia. D. Flexible bronchoscopy is best used for examination of the proximal airways. E. Flexible bronchoscopes have smaller bores than rigid bronchoscopes. ANSWER: E 4. Modern flexible bronchoscopes: A. Allow the operator to visualize sixth-order bronchi B. Are commonly equipped with a cupped forceps C. May produce biopsies that sometimes include bronchial cartilage D. None of the above E. A, B, and C ANSWER: E 5. Biopsy specimens that are obtained in the bronchoscopy suite: A. Should ideally be air-dried before submission to the laboratory B. Can alternatively be placed in fixative solution or transport medium by the bronchoscopist C. Should be wrapped in sterile dry gauze pads before sending them to the laboratory D. Are unsuitable for immunohistochemical studies E. All of the above ANSWER: B
6. Currently, the standard fixative for lung biopsy specimens is: A. Ethylene glycol B. Methacarn C. 10% Formalin D. Bouin solution E. A mixture of 20% formalin and 80% ethanol
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ANSWER: C 7. Which of the following statements about bronchoscopy specimens is TRUE? A. They are subject to relatively little artifact due to biopsy technique. B. Air-drying helps to preserve open alveolar spaces in them. C. The optimal number of tissue pieces in them depends on the disease process. D. Fungal cultures cannot be performed using them. E. All of the above ANSWER: C 8. In transbronchial lung biopsy techniques, which of the following statements is TRUE? A. Cupped forceps are not used. B. The jaws of the forceps should be open when it is first placed in the airway. C. Biopsies are obtained at end-inspiration of the respiratory cycle. D. The pieces of tissue that are obtained have a smooth cylindrical shape. E. Tissue fragments measure 2 to 3 mm in diameter. ANSWER: E 9. In obtaining specimens for cytopathology, which ONE of the following statements regarding the bronchial brushing technique is TRUE? A. It uses an instrument resembling a miniature paintbrush. B. Contents of the brush are washed onto glass slides with ethanol. C. Resulting slides cannot be stained with Wright-Giemsa reagents. D. Papanicolaou stain is often applied to the slides. E. Immediate fixation of slides in 10% formalin is recommended. ANSWER: D 10. Molecular characterization of lung tissue can be accomplished using: A. Bronchial washing specimens B. Transbronchial biopsy specimens C. Open lung biopsy specimens D. All of the above E. None of the above ANSWER: D 11. Bronchoalveolar lavage specimens are obtained: A. After filling the airways of both lungs with sterile saline and waiting 5 minutes B. Only from adult patients C. For purposes of tumor diagnosis D. To evaluate possible lung infections E. From patients who may have surfactant abnormalities ANSWER: D
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Practical Pulmonary Pathology 12. In the transbronchial fine-needle aspiration technique of Wang and Terry, the aspirate sample is washed from the biopsy needle with: A. Air B. Saline C. Plasma D. Ethanol E. Michel solution ANSWER: A 13. Which ONE of the following statements regarding rigid bronchoscopy is TRUE? A. It can be done in an outpatient setting in a physician’s office. B. It is no longer performed in the United States. C. Relatively large foreign bodies can be extracted with it. D. Necrotic lung tumors should not be accessed with it. E. It was introduced as a new method in the year 1925 and abandoned in 1995. ANSWER: C 14. Which of the following statements regarding thoracenteses is TRUE? A. They are performed for relief of symptoms in cases of pleural effusion. B. They yield specimens that can be kept unspoiled at 4°C for several hours. C. They can be used for chemical and enzymatic analyses. D. They are suitably performed in cases of suspected intrapleural tumor. E. All of the above ANSWER: E 15. Why is it advisable for histotechnologists to prepare four to six unstained glass slides of small tissue specimens? A. They can be used later for biochemical analysis of the tissue. B. The medicolegal risk attending these specimens mandates that all of them should be sent out for extramural consultation. C. The tissue can be scraped off the slides to reconstruct the lesion they contain in three dimensions. D. All of the above E. None of the above ANSWER: E 16. In the clinical procedure abbreviated as “VATS,” what does the “V” stand for? A. Virtual B. Vacuum C. Video D. Vesalius E. Vivisection ANSWER: C
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17. Which of the following statements regarding open wedge biopsies of the lungs is/are TRUE? A. Intercollegial consultation is strongly recommended. B. They are performed primarily for the treatment of peripheral lung cancers that measure greater than 5 cm in diameter. C. One biopsy specimen from one lung is acceptable for diagnosis. D. They are inferior to transbronchial biopsies for diagnosis of interstitial lung diseases. E. They can now be done without general anesthesia. ANSWER: A 18. Which of the following methods can be performed very successfully using paraffin blocks of lung tissue? A. Electron microscopy B. Flow cytometry C. Molecular cytogenetic studies D. Microbiologic cultures E. All of the above ANSWER: C 19. What is the recommended method for performing frozen section microtomy on fresh lung tissue? A. Freezing a 5- to 6-mm thick slab of tissue cut with a fresh scalpel B. Embedding the fresh tissue in agar C. Infusing the specimen with Bouin solution using a needle and syringe D. Slow-freezing the specimen with a drop in temperature of no more than 5°C per minute E. Filling the airways with latex before cutting the sections ANSWER: A 20. Which of the following techniques can be used to optimize fixation and histologic visualization of atelectatic lung tissue? A. Shaking the specimen in a sealed container that is half full of fixative B. Removing all surgical staples before fixation and prosection C. Adding a small volume of carbonated water to the fixative solution D. Insufflating the tissue with fixative using a needle and syringe, after removing surgical staples E. All of the above ANSWER: E
Pulmonary Function Testing for Pathologists lung disease. The increased FEV1 to FVC ratio and loss of DLCO points to a parenchymal restriction. This is despite the small contribution from obesity, all consistent with idiopathic pulmonary fibrosis or other fibrotic lung disease.
Case 1 54-year-old male former smoker with shortness of breath
Height 69 in
Weight 135 lbs
Case 3
Actual
Pred
%Pred
TLC liters
7.33
6.85
107
FRC liters
5.63
3.81
146
A 54-year-old male with a viral prodrome with respiratory and gastrointestinal symptoms several days earlier. Some tingling noted in extremities. Developing progressive shortness of breath with exertion.
RV
4.59
2.23
206
FVC liters
2.87
1.50
62
FEV1 liters
1.80
1.26
53
FEV1/FVC% DLCO
66 6.09
27.62
22
Discussion Case 1 demonstrates incremental increase in the lung volumes. The body plethysmography measures the functional residual capacity (FRC) with algebraic determination of the total lung capacity (TLC) and residual volume (RV). This case clearly demonstrates elevated lung volumes in both the FRC and RV. The TLC is within normal parameters, but overall these findings suggest an obstructive process. The forced expiratory volume (FEV1) and FVC are reduced especially in relationship to the size of the lungs in this case and the ratio indicates airway obstruction. Most will use a ratio cutoff of less than 0.7. Lastly the diffusion capacity of carbon monoxide (DLCO) is markedly reduced relative to all other measures. In total this case represents chronic obstructive pulmonary disease (COPD) consistent with emphysema. Emphysema leads to loss of alveoli and capillary beds. The loss of tissue leads to loss of elastic recoil and loss of capillary beds leads to loss of DLCO.
Case 2 A 70-year-old male former smoker with shortness of breath Height 71 in
Weight 204 lbs %Pred
Actual
Pred
TLC liters
4.35
6.28
69
FRC liters
2.30
3.55
64
RV
1.68
2.39
70
FVC liters
2.52
3.88
64
FEV1 liters
2.16
2.61
82
15.77
23.97
FEV1/FVC% DLCO
Weight 135 lbs %Pred
Actual
Pred
TLC liters
5.27
6.85
FRC liters
3.73
3.81
98
RV
2.59
2.23
116
FVC liters
1.72
2.87
60
FEV1 liters
1.44
1.80
80
26.05
27.62
77
FEV1/FVC% DLCO
83 94
Discussion This case demonstrates a step-up pattern in lung volumes. The FRC is normal, and the TLC is reduced and the RV increased. By definition the patient did not, or could not, inhale all the way in to TLC or blow out to full RV. The FVC is low because the patient could not exhale for full 6 seconds. The DLCO is normal and indicates no parenchymal damage. The two options are either “poor” effort on the part of the patient or a true neuromuscular weakness. Additional information that could be obtained would be to look for an increase in the expiratory reserve volume, which is the remaining space after full exhalation. Lastly, obtaining a negative inspiratory force (NIF) or positive expiratory force (PEF) would confirm lower levels than expected in a true neuromuscular weakness. This is a case of Guillain-Barré syndrome. As the patient’s FVC drops to less than 2 L, concerns increase for signs of respiratory failure.
Case 4 A 44-year-old female presents with progressive shortness of breath, fatigue, and dizziness. She notes swelling in her legs over several months as well. Height 66 in
Weight 165 lbs
Actual
Pred
%Pred
TLC liters
4.93
5.35
92
FRC liters
2.63
2.98
88
RV
1.66
1.76
94
FVC liters
2.80
3.69
76
FEV1 liters
2.24
3.04
74
85 65
Discussion Case 2, in contrast, has similar FEV1 and forced vital capacity (FVC) reductions. However, the lung volumes are universally reduced with a slightly more pronounced reduction in the FRC relative to the TLC and RV suggesting an obesity contribution. The flows are reduced as noted, but now the ratio is elevated, suggesting increased elastic recoil instead of airway obstruction. Lastly, the DLCO is proportionately reduced to the loss of volume. In total, the volumes represent a restrictive
Height 71 in
2
FEV1/FVC% DLCO
80 18.86
29.48
64
20.e3
Practical Pulmonary Pathology Discussion In this example, although there is a small disproportionate decreased in FRC relative to TLC and RV, all the volumes are within normal range. Similarly, the flows are all within normal range. The DLCO is markedly reduced. The differential includes anemia and causes of loss of capillary beds, with examples, such as fibrosis, pulmonary embolism, or pulmonary hypertension. The chronic history and signs of edema suggest pulmonary hypertension.
Case 5 A 44-year-old female with scleroderma presents with progressive shortness of breath, fatigue, and dizziness. She notes swelling in her legs over several months as well. Height 66 in
Weight 180 lbs %Pred
Actual
Pred
TLC liters
4.01
5.35
75
FRC liters
2.03
2.98
68
RV
1.27
1.76
72
FVC liters
2.25
3.69
68
FEV1 liters
2.04
3.04
74
12.96
29.48
FEV1/FVC% DLCO
20.e4
89 44
Discussion The conditions of the prior case have been changed to illustrate multiple contributions to this abnormal study. The volumes are reduced and more so for the FRC, reflecting this patient’s increased body mass index. However, a true parenchymal disorder also exists with values less than the 80% and accompanying reductions in the DLCO. Similarly, the FEV1 to FVC ratio is markedly elevated, suggesting increased elastic recoil from parenchymal fibrosis. Lastly, the similar right heart symptoms suggest concurrent pulmonary hypertension. This fits well with a history of scleroderma that gives pulmonary fibrosis and pulmonary hypertension, providing the lower observed DLCO than in the previous study.
2
Pulmonary Function Testing for Pathologists Imre Noth, MD
Lung Volumes 15 Tools to Measure Volumes 16 Interpretation of Lung Volumes 17 Flows 17 Airway Resistance 17 Respiratory Muscle Strength 17 Diffusion Capacity 18 Summary 19 References 19
As the name implies, pulmonary function testing provides quantification of pulmonary physiologic function. By definition this information is disease independent and static, representing a point in time evaluation. Nonetheless, this information can be very helpful for building a differential diagnosis. In fact, many pulmonary diseases are clinical syndromes and without either a definitive molecular marker for disease or without unique defining functional features. These diseases therefore often require integration of histopathology with radiologic patterns, clinical context, and functional status. Pulmonary function tests (PFTs) often provide the first diagnostic tool that helps guide a clinical pulmonologist in creating a filing system for a possible differential. This chapter will focus on the basic elements that comprise a full set of PFTs. In general, these consist of lung volumes (TLC, FRC, RV; see Table 2.1 for a list of abbreviations used in this chapter), lung flows by spirometry (FVC, FEV1, FEF25-75), airway resistance (Raw), and capillary bed assessment (DLCO). Correct interpretation of PFTs requires that the patient obtained values be read in comparison with appropriate reference values, resulting in a reporting method of “percent of predicted.” Numerous regression equations have been proposed, and used, all commonly adjust for age, gender, height, and race.1-3 The European Respiratory Society and the American Thoracic Society have published guidelines regarding the conduct of measuring and interpreting PFTs.1,4-6 Furthermore, PFTs provide quantification of the severity of the lung impairment and can be used to evaluate for change in lung function
over time. This change over time in function may be age related or represents deterioration related to a disease state or, potentially, improvement related to institution of therapy. The approach of this chapter is therefore to outline how the functional data from PFTs can help guide that differential. Fundamentally, lung physiologic function will be normal, restrictive, or obstructive. Restriction implies reduction in lung volumes—size of the lungs. Obstructive implies reduced air flows, mostly secondary to narrowing of the airways, such as in asthma,7 or reduced elastic recoil, such as from emphysema,8 leading to greater exhalation times. We will start with simple categorization of normal compared with restrictive and obstructive patterns. Although patterns may be mixed, for purposes of organization, one must be predominant. In truth, many techniques and a plethora of available equipment make this arena very diverse. Therefore each part has pros and cons and must be considered in the interpretation of PFTs. After all the parts are established, pattern recognition is a key element, as with many composite tests in medicine. This chapter seeks to provide a clear understanding of the fundamentals of PFTs. Basic interpretation should allow the pathologist to independently provide additional functional context to their differentials on evaluation of histopathology of lung tissue to better inform the clinician for a diagnosis.
Lung Volumes The first objective of a full set of PFTs involves determination of the size of the lungs or the lung volumes. Almost all pulmonary diseases that affect function can be divided into three simple categories. Obstructive lung diseases will all eventually lead to increased lung volumes. This is because ultimately air gets in but cannot get back out. This effect can result in static air trapping, such as in emphysema, or dynamic air trapping, as in reversible airway disease like asthma.9 Restrictive lung diseases will all lead to some measure of reduction in lung volumes because the lung themselves are stiffer3 or the chest wall either will not allow for expansion (i.e., chest wall restriction) or cannot expand fully (i.e., neuromuscular weakness10). Normal lung size implies no clinical deficit from obstruction or restriction. This leaves the pulmonary vasculature or, alternatively, causes external to the lung as potentially causal for any presenting symptomatology. 15
Practical Pulmonary Pathology The lung volumes and lung capacities refer to volumes associated with different phases of the respiratory cycle. Although the volumes can be directly measured, the available capacities are inferred from the lung volumes. There are a number of volumes that can be measured (Table 2.1 and Fig. 2.1); however, three measures (TLC, FRC, RV) are key in determining restriction versus obstruction. The remaining volumes and capacities represent measures for compartmentalization of the respiratory cycle functions (IRV, TV, ERV, RV, IC, and VC).
Tools to Measure Volumes There are several methodologies to attaining lung volumes. The “gold standard” involves body box plethysmography.2 This method uses Boyle’s
law (PV = nRT) to measure changes in pressure to determine lung volumes assuming the temperature is constant. It is important to note that this measure is ideally conducted with the patient breathing normally and therefore measures the functional residual capacity (FRC). Determination of the total lung capacity and residual volume are therefore determined by simple algebraic addition of inspiratory capacity (FRC + IC = TLC) and subtraction of the vital capacity (TLC − VC = RV). Therefore these last two volumes should be interpreted in light of the quality of the IC and VC. Although this approach is the most accurate, it also involves the largest and most expensive piece of equipment. Therefore many labs will use a closed-circuit technique with a helium dilution or nitrogen washout technique. These techniques make assumptions regarding the equilibration of gas concentrations in the portions
Table 2.1 Common Pulmonary Function Test Terminology TLC = RV + VC = FRC + IC
TLC
Total lung capacity
The volume in the lungs at maximal inflation
FRC
Functional residual capacity
The volume in the lungs at end expiration
RV
Residual volume
The volume that remains after full exhalation
ERV
Expiratory reserve volume
The volume that remains after normal tidal respiratory exhalation above the RV
IRV
Inspiratory reserve volume
The maximal additional inhalable volume starting after a normal tidal volume
IRV = IC − TV
IC
Inspiratory capacity
The maximal volume for inhalation starting at FRC
IC = TV + IRV
IVC
Inspiratory vital capacity
VC
Vital capacity
The total available volume from RV to TLC
TLC − RV = VC
TV
Tidal volume
The normal respiratory cycle volume
FVC
Forced vital capacity
Maximal volume attained on dynamic forced expiration beginning at TLC
FEV1
Forced expiratory volume
Maximal volume attained on forced exhalation in first second
in first second FEV1/FVC
the ratio of the % predicted
Reveals if increased or decreased flows
NIF
Negative inspiratory force
Reveals force generated on inspiration
PEF
Positive expiratory force
Reveals force generated on expiration
DLCO
Diffusion capacity of carbon monoxide
Measures the uptake of CO as surrogate for capillary beds
TLC
Volume Compliance of chest wall
TV FRC ERV Compliance of lung RV
Pressure
Normal
Figure 2.1 The volumes of the lung are determined by the pressure-volume relationship between the chest wall, which exerts negative force on the intrathoracic shape as the ribs are built like a “bow” of a bow and arrow set, and the lung, which, like a balloon, has elastic recoil that exerts a positive force to keep it small. The neutral point is presented by the balance of these forces at the functional residual capacity (FRC) and where we spend the majority of our time when not actively inhaling or exhaling. ERV, Expiratory reserve volume; RV, residual volume; TLC, total lung capacity, TV, tidal volume. 16
Pulmonary Function Testing for Pathologists of the lung that communicate with the breathing circuit.2 The key limitation of these last two approaches is that areas of the lung that involve trapped air (bullous disease in example) do not necessarily communicate with the breathing circuit and therefore result in an underestimation of the total volume.
Interpretation of Lung Volumes The average TLC will be approximately 6 L11; however, it is critical to recognize that these volumes are dependent on the height, age, gender, and race of the patient.2 A person only 5 ft tall will obviously have much smaller lungs than another individual more than 6 feet tall. Therefore all lung function testing is adjusted for these variables using various regression equations from known populations to normalize values to a percent of predicted, with 100% representing the ideal normal. Because of the high degree of variability of what constitutes “normal,” most interpreters consider the confidence interval of normal and ±20%. Therefore normal volumes range from 80% to 120% of predicted. Thus, by definition, pulmonary function testing commonly ruled as “obstructive” would have lung volumes that are elevated beyond 120% of predicted. This is where pattern recognition comes into play. Although elevation in TLC is used for the primary interpretation, elevation in all three key lung volumes is expected in classic obstructive lung disease, such as emphysema and chronic bronchitis. There are three basic restrictive patterns. The first is a disproportionate reduction in the FRC (i.e., 60% of predicted) greater than either the TLC (80% of predicted) or RV (80% of predicted). This pattern suggests a chest wall involvement, such as an obesity restriction.12 Most methods, which are outlined in subsequent text, actually measure the volume at FRC. This is because the FRC is the normal resting state, whereas measuring at TLC or RV would be very uncomfortable on the patient. As the TLC and RV are algebraically derived from the FRC, this pattern represents a shift in the resting relationship between the chest wall and the lung compliance (Fig. 2.2). The patient is able to overcome the decrease in FRC from the increased weight on the chest with normal respiratory muscle strength to help partially normalize the latter two values (TLC and RV). The second pattern involves a reduced TLC (80% of predicted), normal FRC (100% of predicted), and increased RV (120% of predicted).10,13 This pattern suggests weakness or poor effort. Again, because the actual number derived is the FRC, the failure to reach TLC on inspiration or RV on expiration while maintaining a normal FRC and therefore chest wall and lung compliance relationship leads to a differential diagnosis of weakness or poor effort (failure to sufficiently perform the test). The third pattern involves equal reduction in all volumes (TLC, FRC, and RV all at 60% of predicted).3 This pattern suggests an intrinsic problem with the lung parenchyma or fibrosis of some kind. The fibrosis leads to increased elastic recoil that causes the lung compliance curve to shift from stiffness, shrinking the size of the lung. Recognition of these patterns helps to outline a differential for the pathologist.
Flows The vast majority of testing will involve spirometry and often spirometry only. Basically, the spirometry measures flow or how good air leaves the lung. Furthermore, as a measure of rate, the flow over time determines the volume.1 Spirometry provides the origin of PFTs. This active dynamic maneuver provides insights into the size of the lungs in the FVC and the obstructive or restrictive nature. These are best revealed by the flow volume loops. Understanding the origins is a fundamental step. The original bell spirometer consists of an upside-down drum spinning on an axle in a
tub of water (Fig. 2.2A). The patient then blows through a hose, which goes into the water and the drum so that when air is blown in, the drum rises on exhalation and falls in inspiration. As the drum spins, a pen can then draw the rise and fall over time on a paper wrapped around the drum. This change in volume over time is a flow rate. It is therefore important to remember that these are not total volumes but flows as they relate to the breathing cycle. With that in mind, spirometry provides several important measures. The patient starts the cycle from the neutral resting position of the FRC (Fig. 2.2B). The first step is inhaling fully to TLC. This provides the IC. Then the patient is instructed to exhale fully for as long and as hard as he or she can. Once the volume plateaus, this provides the FVC. By definition this number is effort dependent, in that a minimum time of exhalation is required. The ATS standard is a minimum of 6 seconds, and some have advocated for an FVC6 as a standard instead of the FVC (Fig. 2.2C).1,14,15 As with all pulmonary function testing, these values are also adjusted for age, gender, and race and normalized to a percent of predicted value. However, the flows should always be taken in context in relationship to the volumes. For example, a patient with a pneumonectomy should not be expected to attain the same flow as one without. Therefore the number may be reduced and not necessarily from restriction or obstruction. The FEV1 is the portion of the curve on exhalation attained in the first second (Fig. 2.3). A little counterintuitively, this number is effort independent. Although the patient needs to blow as hard as he or she can, the amount that comes out is dependent on two factors, both of which are intrinsic to the lung. The first is lung compliance or elastic recoil. In other words, how elastic is the lung? Imagine a balloon being released. The maximal flow is the initial portion and dependent on the stretch on the balloon and not any external compression (i.e., chest wall squeeze). The second is the diameter of the opening of the balloon, or in the case of the lungs, the airways. If the airways are constricted, then the flow rate will be reduced. Therefore the FEV1 is informative regarding the level of obstruction, particularly when we evaluate the FEV1 over the FVC to reveal the elastic recoil of the lung. But the example of the pneumonectomy patient still applies for the FEV1 as well, and the results must be taken in context. Briefly the FEF25–75 assesses the middle part of the curve on the exhalation and provides insights into the mid and small airways disease. Perhaps the most valuable part of the spirometry is the loop itself. The inspiratory limb provides the IC, and then the dynamic single exhalation maneuver provides the FEV1 and FVC together. Therefore if the loop is concave, the flow rate tapers off sharply, indicating obstruction. If the loop is convex, then a greater proportion of the flow than expected is attained more rapidly, suggesting increased elastic recoil and restriction. Modern spirometry uses a pneumotach device, which usually uses a change in pressure to measure airflow rates, allowing for much smaller devices.16
2
Airway Resistance This can be measured similarly to the body box maneuver. The Raw is a linear regression equation using the change in resistance with changing flows. It reflects the large central airways and is most useful as additional information for an obstructive lung disease process.
Respiratory Muscle Strength Two simple maneuvers are conducted in evaluation of respiratory muscles.13 The negative inspiratory force (NIF) measures the pressure generated by patient on inhalation against a closed system. The positive expiratory force (PEF) accomplishes the same but on exhalation. These 17
Practical Pulmonary Pathology Forced expiratory vital capacity maneuver
Patient inspires maximally to total lung capacity, then exhales into spirometer as forcefully, as rapidly, and as completely as possible
A
Vital capacity
Tidal volume
Functional residual capacity
Total lung capacity
Expiratory reserve volume
Residual volume
B 7
Normal
Liters (BTPS)
6 5
Restricted
4 3
Obstructed
2 1 0
C
0
1
2
3
4
5
6
Seconds
Figure 2.2 (A) Demonstration of a classic bell spirometer. (B) The tracing on the “spinning” drum of a bell spirometer, using flow over time, yields the various volumes and demonstrates where and how the algebraic additions give the total volumes. (C) The flow in liters versus time in seconds demonstrates the differences between normal and the reduced states of restricted or obstructed disease. A greater proportion exits within the first second for restriction and smaller proportion for obstructive diseases.
values are very effort dependent and, although predictions are used for normal, which range from 60 to 120 cm H2O, the important values are when these are very low. Concerns are often raised when these numbers fall below 40 because it is not until these low and lower values that an impact is reflected in the FVC. 18
Diffusion Capacity The blood freely and rapidly takes up carbon monoxide (CO).17 Therefore when a patient is asked to inhale a concentration of CO, the amount exhaled will reveal the level of uptake by the blood flow in the lung.
Pulmonary Function Testing for Pathologists
V (L/s)
Exp.
Insp.
Obstructed
7 6 5 4 3 2 1 0 1 2 3 4 5 6 100
0 100
Normal
0 100
Restricted
2
0
Vital capacity (%) Figure 2.3 Flow volume loops. The obstructed pattern demonstrates concavity of the expiratory (top portion) limb of the maneuver, whereas the restricted pattern is more convex. Both reveal a lower expiratory flow rate and total volume than expected in the normal loop. Left, obstructive pulmonary disease; center, normal; right, restricted pulmonary disease; Exp., Expiratory; Insp., inspiratory.
This functions as surrogate for how well the lung exchanges gases. The critical element of that blood flow is represented by the capillary bed. So, although there are a number of eclectic reasons for a decreased DLCO, the primary parenchymal concern is a “loss of capillary beds,” most commonly through alveolar destruction, but also through replacement by a fibrotic process. Alternatives include anemia because the amount of total hemoglobin in the blood cells is what determines the uptake of the CO. Similarly, acute congestive heart failure will lead to spillage of hemoglobin into the alveolar spaces and elevate the uptake of CO, at least transiently with acute pulmonary edema, and restriction from chronic congestive heart failure is possible over time.18 Representative examples of obstructive lung diseases include asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis,19 and restrictive lung diseases include interstitial pneumonitis (UIP, NSIP RB-ILD, DIP) and occupational lung diseases (silicosis, asbestosis, coal worker’s pneumoconiosis). You will notice that a few entities will afflict both the parenchyma and airways, leading to mixed restrictive and obstructive patterns. These include sarcoidosis, hypersensitivity pneumonitis, lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell histiocytosis (PLCH), constrictive bronchiolitis, and combined COPD and ILD.
Summary Pulmonary function testing is a simple and available test that is used in the diagnosis and monitoring of restrictive and obstructive lung diseases. Restrictive lung diseases consist of reduced lung volumes with preserved or increased flows. Obstructive lung diseases consist of increased lung volumes with reduced flows. Measurement of diffusion capacity may enhance the diagnostic and prognostic efficacy of simple spirometry. Although PFTs aid in differentiating the physiologic nature of the disease, they remain nonspecific. Integration of radiologic, histopathologic, and clinical signs and symptoms are required for a definitive diagnosis. References 1. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-338. doi:10.1183/09031936.05.00034805.
2. Wanger J, Clausen JL, Coates A, et al. Standardisation of the measurement of lung volumes. Eur Respir J. 2005;26(3):511-522. doi:10.1183/09031936.05.00035005. 3. Kanengiser LC, Rapoport DM, Epstein H, Goldring RM. Volume adjustment of mechanics and diffusion in interstitial lung disease. Lack of clinical relevance. Chest. 1989;96(5):1036-1042. 4. American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis. 1991;144(5):1202-1218. doi:10.1164/ajrccm/144.5.1202. 5. Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26(5):948-968. doi:10.1183/09031936.05.00035205. 6. Miller MR, Crapo R, Hankinson J, et al. General considerations for lung function testing. Eur Respir J. 2005;26(1):153-161. doi:10.1183/09031936.05.00034505. 7. Gilbert R, Auchincloss JH Jr. The interpretation of the spirogram. How accurate is it for “obstruction”? Arch Intern Med. 1985;145(9):1635-1639. 8. Govaerts E, Demedts M, Van de Woestijne KP. Total respiratory impedance and early emphysema. Eur Respir J. 1993;6(8):1181-1185. 9. Mishima M. Physiological differences and similarities in asthma and copd-based on respiratory function testing. Allergol Int. 2009;58(3):333-340. doi:10.2332/allergolint.09-RAI-0131. 10. Saunders NA, Rigg JR, Pengelly LD, Campbell EJ. Effect of curare on maximum static PV relationships of the respiratory system. J Appl Physiol Respir Environ Exerc Physiol. 1978;44(4): 589-595. 11. Sorensen JB, Morris AH, Crapo RO, Gardner RM. Selection of the best spirometric values for interpretation. Am Rev Respir Dis. 1980;122(5):802-805. doi:10.1164/arrd.1980.122.5.802. 12. Chiang ST, Lee PY, Liu SY. Pulmonary function in a typical case of Pickwickian syndrome. Respiration. 1980;39(2):105-113. 13. Enright PL, Kronmal RA, Manolio TA, Schenker MB, Hyatt RE. Respiratory muscle strength in the elderly. Correlates and reference values. Cardiovascular Health Study Research Group. Am J Respir Crit Care Med. 1994;149(2 Pt 1):430-438. doi:10.1164/ajrccm.149.2.8306041. 14. Redlich CA, Tarlo SM, Hankinson JL, et al. Official American Thoracic Society technical standards: spirometry in the occupational setting. Am J Respir Crit Care Med. 2014;189(8):983-993. doi:10.1164/rccm.201402-0337ST. 15. Akpinar-Elci M, Fedan KB, Enright PL. FEV6 as a surrogate for FVC in detecting airways obstruction and restriction in the workplace. Eur Respir J. 2006;27(2):374-377. doi:10.118 3/09031936.06.00081305. 16. Jenkins SC, Barnes NC, Moxham J. Evaluation of a hand-held spirometer, the Respiradyne, for the measurement of forced expiratory volume in the first second (FEV1), forced vital capacity (FVC) and peak expiratory flow rate (PEFR). Br J Dis Chest. 1988;82(1):70-75. 17. Hughes JM, Pride NB. Examination of the carbon monoxide diffusing capacity (DL(CO)) in relation to its KCO and VA components. Am J Respir Crit Care Med. 2012;186(2):132-139. doi:10.1164/rccm.201112-2160CI. 18. Minasian AG, van den Elshout FJ, Dekhuijzen PN, et al. Pulmonary function impairment in patients with chronic heart failure: lower limit of normal versus conventional cutoff values. Heart Lung. 2014;43(4):311-316. doi:10.1016/j.hrtlng.2014.03.011. 19. Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011;155(3):179-191. doi:10.7326/0003-4819-155-3-201108020-00008.
19
Pulmonary Function Testing for Pathologists
Multiple Choice Questions 1. Which of the following procedures is/are used in modern pulmonary medicine to obtain tissue specimens from the lungs? A. Bronchoscopy B. Video-assisted thoracoscopy C. Fine-needle aspiration D. Surgical wedge biopsy E. All of the above ANSWER: E 2. Which ONE of the following statements is FALSE? A. Procurement of clinical and radiologic information is diagnostically more helpful in neoplastic lung disease, compared with nonneoplastic disorders. B. Specimen size and quality affect the level of diagnostic certainty. C. Descriptive diagnoses are acceptable in lung pathology. D. Fine-needle aspiration biopsy of the lung has acceptable specificity and sensitivity compared with diagnosis of pulmonary neoplasms. E. The marginal quality of any given lung biopsy specimen can be described in the surgical pathology report. ANSWER: A 3. Which ONE of the following statements is TRUE? A. Flexible bronchoscopy began in the United States in the late 1980s. B. Rigid bronchoscopy is no longer performed in Asia. C. Flexible bronchoscopy requires general anesthesia. D. Flexible bronchoscopy is best used for examination of the proximal airways. E. Flexible bronchoscopes have smaller bores than rigid bronchoscopes. ANSWER: E 4. Modern flexible bronchoscopes: A. Allow the operator to visualize sixth-order bronchi B. Are commonly equipped with a cupped forceps C. May produce biopsies that sometimes include bronchial cartilage D. None of the above E. A, B, and C ANSWER: E 5. Biopsy specimens that are obtained in the bronchoscopy suite: A. Should ideally be air-dried before submission to the laboratory B. Can alternatively be placed in fixative solution or transport medium by the bronchoscopist C. Should be wrapped in sterile dry gauze pads before sending them to the laboratory D. Are unsuitable for immunohistochemical studies E. All of the above ANSWER: B
6. Currently, the standard fixative for lung biopsy specimens is: A. Ethylene glycol B. Methacarn C. 10% Formalin D. Bouin solution E. A mixture of 20% formalin and 80% ethanol
2
ANSWER: C 7. Which of the following statements about bronchoscopy specimens is TRUE? A. They are subject to relatively little artifact due to biopsy technique. B. Air-drying helps to preserve open alveolar spaces in them. C. The optimal number of tissue pieces in them depends on the disease process. D. Fungal cultures cannot be performed using them. E. All of the above ANSWER: C 8. In transbronchial lung biopsy techniques, which of the following statements is TRUE? A. Cupped forceps are not used. B. The jaws of the forceps should be open when it is first placed in the airway. C. Biopsies are obtained at end-inspiration of the respiratory cycle. D. The pieces of tissue that are obtained have a smooth cylindrical shape. E. Tissue fragments measure 2 to 3 mm in diameter. ANSWER: E 9. In obtaining specimens for cytopathology, which ONE of the following statements regarding the bronchial brushing technique is TRUE? A. It uses an instrument resembling a miniature paintbrush. B. Contents of the brush are washed onto glass slides with ethanol. C. Resulting slides cannot be stained with Wright-Giemsa reagents. D. Papanicolaou stain is often applied to the slides. E. Immediate fixation of slides in 10% formalin is recommended. ANSWER: D 10. Molecular characterization of lung tissue can be accomplished using: A. Bronchial washing specimens B. Transbronchial biopsy specimens C. Open lung biopsy specimens D. All of the above E. None of the above ANSWER: D 11. Bronchoalveolar lavage specimens are obtained: A. After filling the airways of both lungs with sterile saline and waiting 5 minutes B. Only from adult patients C. For purposes of tumor diagnosis D. To evaluate possible lung infections E. From patients who may have surfactant abnormalities ANSWER: D
20.e1
Practical Pulmonary Pathology 12. In the transbronchial fine-needle aspiration technique of Wang and Terry, the aspirate sample is washed from the biopsy needle with: A. Air B. Saline C. Plasma D. Ethanol E. Michel solution ANSWER: A 13. Which ONE of the following statements regarding rigid bronchoscopy is TRUE? A. It can be done in an outpatient setting in a physician’s office. B. It is no longer performed in the United States. C. Relatively large foreign bodies can be extracted with it. D. Necrotic lung tumors should not be accessed with it. E. It was introduced as a new method in the year 1925 and abandoned in 1995. ANSWER: C 14. Which of the following statements regarding thoracenteses is TRUE? A. They are performed for relief of symptoms in cases of pleural effusion. B. They yield specimens that can be kept unspoiled at 4°C for several hours. C. They can be used for chemical and enzymatic analyses. D. They are suitably performed in cases of suspected intrapleural tumor. E. All of the above ANSWER: E 15. Why is it advisable for histotechnologists to prepare four to six unstained glass slides of small tissue specimens? A. They can be used later for biochemical analysis of the tissue. B. The medicolegal risk attending these specimens mandates that all of them should be sent out for extramural consultation. C. The tissue can be scraped off the slides to reconstruct the lesion they contain in three dimensions. D. All of the above E. None of the above ANSWER: E 16. In the clinical procedure abbreviated as “VATS,” what does the “V” stand for? A. Virtual B. Vacuum C. Video D. Vesalius E. Vivisection ANSWER: C
20.e2
17. Which of the following statements regarding open wedge biopsies of the lungs is/are TRUE? A. Intercollegial consultation is strongly recommended. B. They are performed primarily for the treatment of peripheral lung cancers that measure greater than 5 cm in diameter. C. One biopsy specimen from one lung is acceptable for diagnosis. D. They are inferior to transbronchial biopsies for diagnosis of interstitial lung diseases. E. They can now be done without general anesthesia. ANSWER: A 18. Which of the following methods can be performed very successfully using paraffin blocks of lung tissue? A. Electron microscopy B. Flow cytometry C. Molecular cytogenetic studies D. Microbiologic cultures E. All of the above ANSWER: C 19. What is the recommended method for performing frozen section microtomy on fresh lung tissue? A. Freezing a 5- to 6-mm thick slab of tissue cut with a fresh scalpel B. Embedding the fresh tissue in agar C. Infusing the specimen with Bouin solution using a needle and syringe D. Slow-freezing the specimen with a drop in temperature of no more than 5°C per minute E. Filling the airways with latex before cutting the sections ANSWER: A 20. Which of the following techniques can be used to optimize fixation and histologic visualization of atelectatic lung tissue? A. Shaking the specimen in a sealed container that is half full of fixative B. Removing all surgical staples before fixation and prosection C. Adding a small volume of carbonated water to the fixative solution D. Insufflating the tissue with fixative using a needle and syringe, after removing surgical staples E. All of the above ANSWER: E
Pulmonary Function Testing for Pathologists lung disease. The increased FEV1 to FVC ratio and loss of DLCO points to a parenchymal restriction. This is despite the small contribution from obesity, all consistent with idiopathic pulmonary fibrosis or other fibrotic lung disease.
Case 1 54-year-old male former smoker with shortness of breath
Height 69 in
Weight 135 lbs
Case 3
Actual
Pred
%Pred
TLC liters
7.33
6.85
107
FRC liters
5.63
3.81
146
A 54-year-old male with a viral prodrome with respiratory and gastrointestinal symptoms several days earlier. Some tingling noted in extremities. Developing progressive shortness of breath with exertion.
RV
4.59
2.23
206
FVC liters
2.87
1.50
62
FEV1 liters
1.80
1.26
53
FEV1/FVC% DLCO
66 6.09
27.62
22
Discussion Case 1 demonstrates incremental increase in the lung volumes. The body plethysmography measures the functional residual capacity (FRC) with algebraic determination of the total lung capacity (TLC) and residual volume (RV). This case clearly demonstrates elevated lung volumes in both the FRC and RV. The TLC is within normal parameters, but overall these findings suggest an obstructive process. The forced expiratory volume (FEV1) and FVC are reduced especially in relationship to the size of the lungs in this case and the ratio indicates airway obstruction. Most will use a ratio cutoff of less than 0.7. Lastly the diffusion capacity of carbon monoxide (DLCO) is markedly reduced relative to all other measures. In total this case represents chronic obstructive pulmonary disease (COPD) consistent with emphysema. Emphysema leads to loss of alveoli and capillary beds. The loss of tissue leads to loss of elastic recoil and loss of capillary beds leads to loss of DLCO.
Case 2 A 70-year-old male former smoker with shortness of breath Height 71 in
Weight 204 lbs %Pred
Actual
Pred
TLC liters
4.35
6.28
69
FRC liters
2.30
3.55
64
RV
1.68
2.39
70
FVC liters
2.52
3.88
64
FEV1 liters
2.16
2.61
82
15.77
23.97
FEV1/FVC% DLCO
Weight 135 lbs %Pred
Actual
Pred
TLC liters
5.27
6.85
FRC liters
3.73
3.81
98
RV
2.59
2.23
116
FVC liters
1.72
2.87
60
FEV1 liters
1.44
1.80
80
26.05
27.62
77
FEV1/FVC% DLCO
83 94
Discussion This case demonstrates a step-up pattern in lung volumes. The FRC is normal, and the TLC is reduced and the RV increased. By definition the patient did not, or could not, inhale all the way in to TLC or blow out to full RV. The FVC is low because the patient could not exhale for full 6 seconds. The DLCO is normal and indicates no parenchymal damage. The two options are either “poor” effort on the part of the patient or a true neuromuscular weakness. Additional information that could be obtained would be to look for an increase in the expiratory reserve volume, which is the remaining space after full exhalation. Lastly, obtaining a negative inspiratory force (NIF) or positive expiratory force (PEF) would confirm lower levels than expected in a true neuromuscular weakness. This is a case of Guillain-Barré syndrome. As the patient’s FVC drops to less than 2 L, concerns increase for signs of respiratory failure.
Case 4 A 44-year-old female presents with progressive shortness of breath, fatigue, and dizziness. She notes swelling in her legs over several months as well. Height 66 in
Weight 165 lbs
Actual
Pred
%Pred
TLC liters
4.93
5.35
92
FRC liters
2.63
2.98
88
RV
1.66
1.76
94
FVC liters
2.80
3.69
76
FEV1 liters
2.24
3.04
74
85 65
Discussion Case 2, in contrast, has similar FEV1 and forced vital capacity (FVC) reductions. However, the lung volumes are universally reduced with a slightly more pronounced reduction in the FRC relative to the TLC and RV suggesting an obesity contribution. The flows are reduced as noted, but now the ratio is elevated, suggesting increased elastic recoil instead of airway obstruction. Lastly, the DLCO is proportionately reduced to the loss of volume. In total, the volumes represent a restrictive
Height 71 in
2
FEV1/FVC% DLCO
80 18.86
29.48
64
20.e3
Practical Pulmonary Pathology Discussion In this example, although there is a small disproportionate decreased in FRC relative to TLC and RV, all the volumes are within normal range. Similarly, the flows are all within normal range. The DLCO is markedly reduced. The differential includes anemia and causes of loss of capillary beds, with examples, such as fibrosis, pulmonary embolism, or pulmonary hypertension. The chronic history and signs of edema suggest pulmonary hypertension.
Case 5 A 44-year-old female with scleroderma presents with progressive shortness of breath, fatigue, and dizziness. She notes swelling in her legs over several months as well. Height 66 in
Weight 180 lbs %Pred
Actual
Pred
TLC liters
4.01
5.35
75
FRC liters
2.03
2.98
68
RV
1.27
1.76
72
FVC liters
2.25
3.69
68
FEV1 liters
2.04
3.04
74
12.96
29.48
FEV1/FVC% DLCO
20.e4
89 44
Discussion The conditions of the prior case have been changed to illustrate multiple contributions to this abnormal study. The volumes are reduced and more so for the FRC, reflecting this patient’s increased body mass index. However, a true parenchymal disorder also exists with values less than the 80% and accompanying reductions in the DLCO. Similarly, the FEV1 to FVC ratio is markedly elevated, suggesting increased elastic recoil from parenchymal fibrosis. Lastly, the similar right heart symptoms suggest concurrent pulmonary hypertension. This fits well with a history of scleroderma that gives pulmonary fibrosis and pulmonary hypertension, providing the lower observed DLCO than in the previous study.