Wheezes are high-pitched, continuous sounds generated by airflow through narrowed airways. Causes of such narrowing include airway smooth muscle constriction, edema, secretions, intraluminal obstruction, and collapse because of poorly supported walls. These individual pathophysiologic features are discussed in Chapters 4 through 7. For reasons that are also described later, the diameter of intrathoracic airways is less during expiration than inspiration, and wheezing generally is more pronounced or exclusively heard in expiration. However, because sufficient airflow is necessary to generate a wheeze, wheezing may no longer be heard if airway narrowing is severe. In conditions such as asthma and chronic obstructive pulmonary disease, wheezes originate in multiple narrowed airways and are generally polyphonic, meaning they are a combination of different musical pitches that start and stop at different times during the expiratory cycle. In contrast, wheezing sounds tend to be monophonic when they result from focal narrowing of the trachea or large bronchi. When the site of narrowing is the extrathoracic airway (e.g., in the larynx or the extrathoracic portion of the trachea), the term stridor is used to describe the inspiratory wheezing-like sound that results from such narrowing. Physiologic factors that relate the site of narrowing and the phase of the respiratory cycle most affected are described later in this chapter and shown in Figures 3-20 and 3-21.

Wheezes reflect airflow through narrowed airways.

Although clinicians commonly use the term rhonchi when referring to sounds generated by secretions in airways, examiners use the term in somewhat different ways. The term is used to describe low-pitched continuous sounds that are somewhat coarser than high-pitched wheezing. It is also used to describe the very coarse crackles that often result from airway secretions. As a result, the term is frequently used to describe the variety of noises and musical sounds that cannot be readily classified within the more generally accepted categories of crackles and wheezes but that all appear to have airway secretions as a common underlying cause.

A friction rub is the term for the sounds generated by inflamed or roughened pleural surfaces rubbing against each other during respiration. A rub is a series of creaky or rasping sounds heard during both inspiration and expiration. The most common causes are primary inflammatory diseases of the pleura or parenchymal processes that extend out to the pleural surface, such as pneumonia and pulmonary infarction.

Table 3-1 summarizes some of the pulmonary findings commonly seen in selected disorders affecting the respiratory system. Many of these are mentioned again in subsequent chapters when the specific disorders are discussed in more detail.

Table 3-1

TYPICAL CHEST EXAMINATION FINDINGS IN SELECTED CLINICAL CONDITIONS

^*May be altered by collapse of underlying lung, which will increase transmission of sound.

Although the focus here is the chest examination itself as an indicator of pulmonary disease, other nonthoracic manifestations of primary pulmonary disease may be detected on physical examination. Briefly discussed here are clubbing (with or without hypertrophic osteoarthropathy) and cyanosis.

Clubbing is a change in the normal configuration of the nails and the distal phalanx of the fingers or toes (Fig. 3-1). Several features may be seen: (1) loss of the normal angle between the nail and the skin, (2) increased curvature of the nail, (3) increased sponginess of the tissue below the proximal part of the nail, and (4) flaring or widening of the terminal phalanx. Although several nonpulmonary disorders can result in clubbing (e.g., congenital heart disease with right-to-left shunting, endocarditis, chronic liver disease, inflammatory bowel disease), the most common causes clearly are pulmonary. Occasionally, clubbing is familial and of no clinical significance. Carcinoma of the lung (or mesothelioma of the pleura) is the single leading etiologic factor. Other pulmonary causes include chronic intrathoracic infection with suppuration (e.g., bronchiectasis, lung abscess, empyema) and some types of interstitial lung disease. Uncomplicated chronic obstructive lung disease is not associated with clubbing, so the presence of clubbing in this setting should suggest coexisting malignancy or suppurative disease.

Figure 3-1 Clubbing in a patient with carcinoma of the lung. Curvature of nail and loss of angle between nail and adjacent skin can be seen.

Respiratory system diseases associated with clubbing:

1. Carcinoma of the lung (or mesothelioma of the pleura)

2. Chronic intrathoracic infection

3. Interstitial lung disease

Clubbing may be accompanied by hypertrophic osteoarthropathy, characterized by periosteal new bone formation, particularly in the long bones, and arthralgias and arthritis of any of several joints. With coexistent hypertrophic osteoarthropathy, either pulmonary or pleural tumor is the likely cause of the clubbing, because hypertrophic osteoarthropathy is relatively rare with the other causes of clubbing.

The mechanism of clubbing and hypertrophic osteoarthropathy is not clear. It has been observed that clubbing is associated with an increase in digital blood flow, whereas the osteoarthropathy is characterized by an overgrowth of highly vascular connective tissue. Why these changes occur is a mystery. One interesting theory suggests an important role for stimuli coming through the vagus nerve, because vagotomy frequently ameliorates some of the bone and nail changes. Another theory proposes that megakaryocytes and platelet clumps, bypassing the pulmonary vascular bed and affecting the peripheral systemic circulation, release growth factors responsible for the soft-tissue changes of clubbing.

Cyanosis, the second extrapulmonary physical finding arising from lung disease, is a bluish discoloration of the skin (particularly under the nails) and mucous membranes. Whereas oxygenated hemoglobin gives lighter skin and all mucous membranes their usual pink color, a sufficient amount of deoxygenated hemoglobin produces cyanosis. Cyanosis may be either generalized, owing to a low PO₂ or low systemic blood flow resulting in increased extraction of oxygen from the blood, or localized, owing to low blood flow and increased O₂ extraction within the localized area. In lung disease, the common factor causing cyanosis is a low PO₂, and several different types of lung disease may be responsible. The total amount of hemoglobin affects the likelihood of detecting cyanosis. In the anemic patient, if the total quantity of deoxygenated hemoglobin is less than the amount needed to produce the bluish discoloration, even a very low PO₂ may not be associated with cyanosis. In the patient with polycythemia, in contrast, much less depression of PO₂ is necessary before sufficient deoxygenated hemoglobin exists to produce cyanosis.

Chest Radiography

The chest radiograph, which is largely taken for granted in the practice of medicine, is used not only in evaluating patients with suspected respiratory disease but also sometimes in the routine evaluation of asymptomatic patients. Of all the viscera, the lungs are the best suited for radiographic examination. The reason is straightforward: air in the lungs provides an excellent background against which abnormalities can stand out. Additionally, the presence of two lungs allows each to serve as a control for the other so that unilateral abnormalities can be more easily recognized.

A detailed description of interpretation of the chest radiograph is beyond the scope of this text. However, a few principles can aid the reader in viewing films presented in this and subsequent chapters.

First, the appearance of any structure on a radiograph depends on the structure’s density; the denser the structure, the whiter it appears on the film. At one extreme is air, which is radiolucent and appears black on the film. At the other extreme are metallic densities, which appear white. In between is a spectrum of increasing density from fat to water to bone. On a chest radiograph, the viscera and muscles fall within the realm of water density tissues and cannot be distinguished in radiographic density from water or blood.

Second, in order for a line or an interface to appear between two adjacent structures on a radiograph, the two structures must differ in density. For example, within the cardiac shadow, the heart muscle cannot be distinguished from the blood coursing within the chambers because both are of water density. In contrast, the borders of the heart are visible against the lungs because the water density of the heart contrasts with the density of the lungs, which is closer to that of air. However, if the lung adjacent to a normally denser structure (e.g., heart or diaphragm) is airless, either because of collapse or consolidation, the neighboring structures are now both of the same density, and no visible interface or boundary separates them. This principle is the basis of the useful silhouette sign. If an expected border with an area of lung is not visualized or is not distinct, the adjacent lung is abnormal and lacks full aeration.

Chest radiographs usually are taken in two standard views—posteroanterior (PA) and lateral (Fig. 3-2). For a PA film, the x-ray beam goes from the back to the front of the patient, and the patient’s anterior chest is adjacent to the film. The lateral view is taken with the patient’s side against the film, and the beam is directed through the patient to the film. If a film cannot be taken with the patient standing and the chest adjacent to the film, as in the case of a bedridden patient, then an anteroposterior view is taken. For this view, which is generally obtained using a portable chest radiograph machine in the patient’s hospital room, the film is placed behind the patient (generally between the patient’s back and the bed), and the beam is directed through the patient from front to back. Lateral decubitus views, either right or left, are obtained with the patient in a side-lying position, with the beam directed horizontally. Decubitus views are particularly useful for detecting free-flowing fluid within the pleural space and therefore are often used when a pleural effusion is suspected.

Figure 3-2 Normal chest radiograph. A, Posteroanterior view. B, Lateral view. Compare with Figure 3-3 for position of each lobe.

Knowledge of radiographic anatomy is fundamental for interpretation of consolidation or collapse (atelectasis) and for localization of other abnormalities on the chest film. Lobar anatomy and the locations of fissures separating the lobes are shown in Figure 3-3. Localization of an abnormality often requires information from both the PA and lateral views, both of which should be taken and interpreted when an abnormality is being evaluated. As can be seen in Figure 3-3, the major fissure separating the upper (and middle) lobes from the lower lobe runs obliquely through the chest. Thus it is easy to be misled about location on the basis of the PA film alone; a lower lobe lesion may appear in the upper part of the chest, whereas an upper lobe lesion may appear much lower in position.

Figure 3-3 Lobar anatomy as seen from anterior and lateral views. In anterior views, shaded regions represent lower lobes and are behind upper and middle lobes. Lingula is part of left upper lobe; dashed line between the two does not represent a fissure. LLL = Left lower lobe; LUL = left upper lobe; RLL = right lower lobe; RML = right middle lobe; RUL = right upper lobe.

Both posteroanterior and lateral radiographs are often necessary for localization of an abnormality.

When a lobe becomes filled with fluid or inflammatory exudate, as in pneumonia, it contains water rather than air density and therefore is easily delineated on the chest radiograph. With pure consolidation the lobe does not lose volume, so it occupies its usual position and retains its usual size. An example of lobar consolidation on PA and lateral radiographs is shown in Figure 3-4.

Figure 3-4 Posteroanterior (A) and lateral (B) chest radiographs of patient with left upper lobe consolidation due to pneumonia. Anatomic boundary is best appreciated on lateral view, where it is easily seen that normally positioned major fissure defines lower border of consolidation (compare with Figure 3-3). Part of left upper lobe is spared. (Courtesy Dr. T. Scott Johnson.)

In contrast, when a lobe has airless alveoli and collapses, it not only becomes more dense but also has features of volume loss characteristic for each individual lobe. Such features of volume loss include change in position of a fissure or the indirect signs of displacement of the hilum, diaphragm, trachea, or mediastinum in the direction of the volume loss (Fig. 3-5). A common mechanism of atelectasis is occlusion of the airway leading to the collapsed region of lung, caused, for example, by a tumor, aspirated foreign body, or mucous plug. All the aforementioned examples reflect either pure consolidation or pure collapse. In practice, however, a combination of these processes often occurs, leading to consolidation accompanied by partial volume loss.

Figure 3-5 Posteroanterior (A) and lateral (B) chest radiographs demonstrating right upper lobe collapse. A, Displaced minor fissure outlines airless (dense) right upper lobe. B, Right upper lobe is outlined by elevated minor fissure (arrow head) and anteriorly displaced major fissure (long arrow).

When the chest film shows a diffuse or widespread pattern of increased density within the lung parenchyma, it often is useful to characterize the process further, depending on the pattern of the radiographic findings. The two primary patterns are interstitial and alveolar. Although the naming of these patterns suggests a correlation with the type of pathologic involvement (i.e., interstitial, affecting the alveolar walls and the interstitial tissue; alveolar, involving filling of the alveolar spaces), such radiographic-pathologic correlations are often lacking. Nevertheless, many diffuse lung diseases are characterized by one of these radiographic patterns, and the particular pattern may provide clues about the underlying type or cause of disease.

Diffuse increase in density on the radiograph often can be categorized as either alveolar or interstitial.

An interstitial pattern generally is described as reticular or reticulonodular, consisting of an interlacing network of linear and small nodular densities. In contrast, an alveolar pattern appears fluffier, and the outlines of air-filled bronchi coursing through the alveolar densities are often seen. This latter finding is called an air bronchogram and is due to air in the bronchi being surrounded and outlined by alveoli that are filled with fluid. This finding does not occur with a purely interstitial pattern. Examples of chest radiographs that show diffuse abnormality as a result of interstitial disease and alveolar filling are shown in Figures 3-6 and 3-7, respectively.

Figure 3-6 Posteroanterior (A) and lateral (B) chest radiographs of patient with interstitial lung disease. Reticulonodular pattern is present throughout but is most prominent in right lung and at base of left lung.

Figure 3-7 Chest radiograph showing a diffuse alveolar filling pattern, most prominent in middle and lower lung fields.

Two additional terms used to describe patterns of increased density are worth mentioning. A nodular pattern refers to the presence of multiple discrete, typically spherical, nodules. A uniform pattern of relatively small nodules several millimeters or less in diameter is often called a miliary pattern, as can be seen with hematogenous (bloodborne) dissemination of tuberculosis throughout the lungs. Alternatively, the nodules can be larger (e.g., > 1 cm in diameter), as seen with hematogenous metastasis of carcinoma to the lungs. Another common term is ground-glass, used to describe a hazy, translucent appearance to the region of increased density. Although the term can be used to describe a region or a pattern of increased density on a plain chest radiograph, it is more commonly used when describing abnormalities seen on computed tomography (CT) of the chest.

Although the preceding focus on some typical abnormalities provides an introduction to pattern recognition on a chest radiograph, the careful examiner must also use a systematic approach in analyzing the film. A chest radiograph shows not only the lungs; radiographic examination also may reveal changes in bones, soft tissues, the heart, other mediastinal structures, and the pleural space.

Pulmonary Angiography

Pulmonary angiography is a radiographic technique in which a catheter is guided from a peripheral vein through the right atrium and ventricle and into the main pulmonary artery or one of its branches. A radiopaque dye is injected, and the pulmonary arterial tree is visualized on a series of rapidly exposed chest films (Fig. 3-12). This test is primarily used for diagnosing pulmonary embolism. A clot in a pulmonary vessel appears either as an abrupt termination (“cutoff”) of the vessel or as a filling defect within its lumen. Previously, pulmonary angiography was often used when the diagnosis of pulmonary embolism was uncertain after lung scanning, or CTA was inconclusive. However, with advances in CT techniques, a pulmonary angiogram is rarely needed.

Figure 3-12 Normal pulmonary angiogram. Radiopaque dye was injected directly into pulmonary artery, and pulmonary arterial tree is well visualized. Catheter used for injecting dye is indicated by arrow. (Courtesy Dr. Morris Simon.)

The pulmonary angiogram has other uses, including investigation of congenital vascular anomalies and invasion of a vessel by tumor. However, use of the angiogram in these situations is also quite infrequent.

Ultrasonography

The ability of different types of tissue to transmit sound and of tissue interfaces to reflect sound has made ultrasonography useful for evaluating a variety of body structures. A piezoelectric crystal generates sound waves, and the reflected echoes are detected and recorded by the same crystal. Images are displayed on a screen and can be captured for a permanent record.

The heart is the intrathoracic structure most frequently studied by ultrasonography, but the technique is also useful in evaluating pleural disease. In particular, ultrasonography is capable of detecting small amounts of pleural fluid and is often used to guide placement of a needle for sampling a small amount of this fluid. Additionally, it can detect walled-off compartments (loculations) within pleural effusions and distinguish fluid from pleural thickening.

Ultrasonography is capable of localizing the diaphragm and detecting disease immediately below the diaphragm, such as a subphrenic abscess. Ultrasonography is not useful for defining structures or lesions within the pulmonary parenchyma, because the ultrasound beam penetrates air poorly.

Bronchoscopy

Direct visualization of the airways is possible by bronchoscopy, originally performed with a hollow, rigid metal tube, but now much more commonly with a thin, flexible instrument (Fig. 3-13). The flexible instrument transmits images either via flexible fiberoptic bundles (traditional fiberoptic bronchoscope) or more commonly via a digital chip at the tip of the bronchoscope that displays the images on a monitor screen. Because the bronchoscope is flexible, the bronchoscopist can bend the tip with a control lever and maneuver into airways at least down to the subsegmental level.

Figure 3-13 Flexible bronchoscope. Long arrows point to flexible part passed into patient’s airways. Short arrow points to portion of bronchoscope connected to light source. Controls for clinician performing procedure are shown at upper left.

The bronchoscopist can obtain an excellent view of the airways (Fig. 3-14) and collect a variety of samples for cytologic, pathologic, and microbiologic examination. Sterile saline can be injected through a small hollow channel in the bronchoscope and suctioned back into a collection chamber. This technique, called bronchial washing, samples cells and, if present, microorganisms from the lower respiratory tract. When the bronchoscope is passed as far as possible and wedged into an airway before saline is injected, the washings are able to sample the contents of the alveolar spaces; this technique is called bronchoalveolar lavage (BAL).

Figure 3-14 Airways as seen through a fiberoptic bronchoscope. At this level, carina can be seen separating right and left mainstem bronchi. A large endobronchial mass (squamous cell carcinoma of lung) obstructs right mainstem bronchus.

With the flexible bronchoscope, airways are visualized and laboratory samples are obtained.

A long, flexible wire instrument with a small brush at the tip can be passed through the hollow channel of the bronchoscope. The surface of a lesion within a bronchus can be brushed and the cells collected or smeared onto a slide for cytologic examination. Brushes are frequently passed into diseased areas of the lung parenchyma, and the material collected by the bristles is subjected to cytologic and microbiologic analysis.

A needle at the end of a long catheter passed through the bronchoscope can puncture an airway wall and sample cells from lymph nodes or lesions adjacent to the airway. This technique, called transbronchial needle aspiration, can be used to obtain malignant cells from mediastinal lymph nodes in the staging of known or suspected lung cancer. Using an ultrasound probe within the airway during bronchoscopy (endobronchial ultrasound) can help the bronchoscopist localize mediastinal lymph nodes external to the airway and therefore greatly assist with accurate needle placement into the node for transbronchial needle aspiration.

With a small biopsy forceps passed through the bronchoscope, the clinician can extract a biopsy specimen from a lesion visualized on the bronchial wall (endobronchial biopsy). The forceps can also be passed through a small bronchus into the lung parenchyma to obtain a small specimen of lung tissue. This procedure, known as a transbronchial biopsy, yields specimens that are small but have a sizable number of alveoli. Fluoroscopy can be used during the procedure to better localize the position of the biopsy forceps relative to the desired biopsy site, either a discrete lesion or an area representative of more diffuse disease.

There are many indications for bronchoscopy, usually with a flexible instrument, although the rigid instrument is used under some circumstances. When appropriate, the flexible instrument is preferred because the procedure can be performed using only mild sedation and the patient need not be hospitalized. In contrast, rigid bronchoscopy is performed only under general anesthesia. Some indications for bronchoscopy include (1) evaluation of a suspected endobronchial malignancy, (2) sampling of an area of parenchymal disease by BAL, brushings, or biopsy, (3) evaluation of hemoptysis, and (4) removal of a foreign body (with special instruments that can be passed through the bronchoscope and are capable of retrieving objects). A variety of newer therapeutic modalities are being delivered to the airways via either flexible or rigid bronchoscopic techniques. These modalities include laser techniques for shrinking endobronchial tumors causing airway obstruction; placement of stents to maintain patency of airways having a compromised or obstructed lumen; procedures for dilation of strictures; placement of radioactive seeds directly into malignant airway lesions (brachytherapy); and delivery of electric current (electrocautery), low temperature (cryotherapy), or certain wavelengths of light (photodynamic therapy) to endobronchial masses. Deployment of these novel therapeutic opportunities has spawned a relatively new and rapidly evolving area of subspecialization within pulmonary medicine called interventional pulmonology.

During the past 40 years or so, bronchoscopy has become a common and useful technique in evaluating and managing pulmonary disease. Even though the physician who first suggested placing a tube into the larynx and bronchi was censured in 1847 for proposing a technique that is “an anatomical impossibility and an unwarrantable innovation in practical medicine,” bronchoscopy generally is well tolerated, and complications are infrequent.

Evaluation on a Microscopic Level

Microscopy often provides the definitive diagnosis of pulmonary disease suggested by the history, physical examination, or imaging of the chest. Several types of disorders are particularly amenable to diagnosis by microscopy: lung tumors (by either histology or cytology), pulmonary infection (by microscopic identification of a specific organism), and a variety of miscellaneous pulmonary diseases, particularly those affecting the interstitium of the lung (by histology). Frequently, when a diagnosis is uncertain, the same techniques are used to obtain samples that are processed both for histologic (or cytologic) examination and for identification of microorganisms. This section provides a discussion of how specimens are obtained and then considers how the specimens are processed.

Obtaining Specimens

The three main types of specimens the physician uses for microscopic analysis in diagnosing the patient with lung disease are (1) tracheobronchial secretions, (2) tissue from the lung parenchyma, and (3) fluid or tissue from the pleura. A number of methods are available for obtaining each of these types of specimens, and knowledge of the yield and the complications determines the most appropriate method.

The easiest way to obtain a specimen of tracheobronchial secretions is to collect sputum expectorated spontaneously by the patient. The sample can be used for identifying inflammatory or malignant cells and for staining (and culturing) microorganisms. Collecting sputum sounds simple, but it presents several potential problems. First, the patient may not have any spontaneous cough and sputum production. If this is the case, a strong cough that produces sputum frequently can be induced by having the patient inhale an irritating aerosol, such as hypertonic saline. Second, what is thought to be sputum originating from the tracheobronchial tree frequently is either nasal secretions or “spit” expectorated from the mouth or the back of the throat. Finally, as a result of passage through the mouth, even a good, deep sputum specimen is contaminated by the multiplicity of microorganisms that reside in the mouth. Because of this contamination, care is required in interpreting the results of sputum culture, particularly with regard to the normal flora of the upper respiratory tract. Despite these limitations, sputum remains a valuable resource when looking for malignancy and infectious processes such as bacterial pneumonia and tuberculosis.

Tracheobronchial secretions also can be obtained by two other routes: transtracheal aspiration and bronchoscopy. With transtracheal aspiration, a small plastic catheter is passed inside (or over) a needle inserted through the cricothyroid membrane and into the trachea. The catheter induces coughing, and secretions are collected either with or without the additional instillation of saline through the catheter. This technique avoids the problem of contamination by mouth and upper airway flora. It also allows collection of a sample even when the patient has no spontaneous sputum production. However, the technique is not without risk. Bleeding complications and, to a lesser extent, subcutaneous emphysema (air dissecting through tissues in the neck) are potentially serious sequelae. Because of these potential complications, the availability of alternative methods of sampling, and physicians’ inexperience with the procedure, transtracheal aspiration is now rarely performed.

Tracheobronchial secretions are provided by:

1. Expectorated sputum

2. Transtracheal aspiration

3. Flexible bronchoscopy

Bronchoscopy, generally with a flexible instrument, is a suitable way to obtain tracheobronchial secretions. It has the additional benefit of allowing visualization of the airways. Bronchoscopy has distinct advantages in collecting material for cytologic analysis because specimens can be collected from a localized area directly visualized with the bronchoscope. However, because the instrument passes through the upper respiratory tract, collection of specimens for culture is subject to contamination by upper airway flora. Specially designed systems with a protected brush can decrease contamination, and quantitating the bacteria recovered can be helpful in distinguishing upper airway contamination from true lower respiratory infection.

BAL has become an increasingly popular method for obtaining specimens from the lower respiratory tract. The fluid obtained by BAL has been used quite effectively for detecting P. jiroveci, particularly in patients with AIDS. In some diffuse parenchymal lung diseases (see Chapters 9 and 11), analysis of the cellular and biochemical components of BAL may provide information that is useful diagnostically and for research about basic disease mechanisms.

As is true of tracheobronchial secretions, tissue specimens for microscopic examination can be collected in numerous ways. A brush or a biopsy forceps can be passed through a bronchoscope. The brush is often used to scrape cells from the surface of an airway lesion, but it can also be passed more distally into the lung parenchyma to obtain specimens directly from a diseased area. The biopsy forceps is used in a similar fashion to sample tissue either from a lesion in the airway (endobronchial biopsy) or from an area of disease in the parenchyma (transbronchial biopsy, so named because the forceps must puncture a small bronchus to sample the parenchyma). In the case of bronchial brushing, the specimen that adheres to the brush is smeared onto a slide for staining and microscopic examination. For both endobronchial and transbronchial biopsies, the tissue obtained can be fixed and sectioned, and slides can be made for subsequent microscopic examination.

A lesion or diseased area in the lung parenchyma can be reached with a needle through the chest wall. This type of biopsy, called a percutaneous needle biopsy, is typically performed using simultaneous guidance by CT imaging. Depending on the type of needle used, a small sample may be aspirated or taken by biopsy. Bleeding and pneumothorax are potential complications, just as they are for a transbronchial biopsy with a bronchoscope.

Lung biopsy specimens can be obtained by:

1. Flexible bronchoscopy

2. Percutaneous needle aspiration or biopsy

3. Video-assisted thoracic surgery

4. Open surgical procedure

Lung tissue is frequently obtained by a surgical procedure involving an approach through the chest wall. Traditionally, a surgeon made an incision in the chest wall, allowing direct visualization of the lung surface and removal of a small piece of lung tissue. This type of open lung biopsy has largely been supplanted by a less invasive procedure called thoracoscopy (video-assisted thoracic surgery or VATS). Video-assisted thoracic surgery involves placement of a thoracoscope and biopsy instruments through small incisions in the chest wall; a high-quality image obtained through the thoracoscope can be displayed on a monitor screen. The surgeon uses the video image as a guide for manipulating the instruments to obtain a biopsy sample of peripheral lung tissue or to remove a peripheral lung nodule.

Finally, fluid in the pleural space is frequently sampled in the evaluation of a patient with a pleural effusion. A small needle is inserted through the chest wall and into the pleural space, and fluid is withdrawn. The fluid can be examined for malignant cells and microorganisms. Chemical analysis of the fluid (see Chapter 15) often provides additional useful diagnostic information. A biopsy specimen of the parietal pleural surface (the tissue layer lining the pleural space) also may be obtained either blindly, with a special needle passed through the chest wall, or under direct visualization using a thoracoscope. The tissue can be used for microscopic examination and microbiologic studies.

Processing Specimens

Once specimens are obtained, the techniques of processing and types of examination performed are common to those used for many types of tissue and fluid specimens.

Diagnosis of pulmonary infections depends on smears and cultures of the material obtained, such as sputum, other samples of tracheobronchial secretions, or pleural fluid. The standard Gram stain technique often allows initial identification of organisms, and inspection may reveal inflammatory cells (particularly polymorphonuclear leukocytes) and upper airway (squamous epithelial) cells, the latter indicating contamination of sputum by upper airway secretions. Final culture results provide definitive identification of an organism, but the results must always be interpreted with the knowledge that the specimen may be contaminated, and that what is grown is not necessarily causally related to the clinical problem.

Specimens can be processed for staining and culture of microorganisms and for cytologic and histopathologic examination.

Identification of mycobacteria, the causative agent for tuberculosis, requires special staining and culturing techniques. Mycobacteria are stained by agents such as carbolfuchsin or auramine-rhodamine, and the organisms are almost unique in their ability to retain the stain after acid is added. Hence, the expression acid-fast bacilli is used commonly when referring to mycobacteria. Frequently used staining methods are the Ziehl-Neelsen stain or a modification called the Kinyoun stain. A more sensitive and faster way to detect mycobacteria involves use of a fluorescent dye such as auramine-rhodamine. Mycobacteria take up the dye and fluoresce and can be detected relatively easily even when present in small numbers. Because mycobacteria grow slowly, they may require 6 to 8 weeks for growth and identification on culture media.

Organisms other than the common bacterial pathogens and mycobacteria often require other specialized staining and culture techniques. Fungi may be diagnosed by special stains, such as methenamine silver or periodic acid–Schiff stains, applied to tissue specimens. Fungi also can be cultured on special media favorable to their growth. P. jiroveci, a pathogen now classified as a unique category of fungi (see Chapter 25) and most common in patients with impaired defense mechanisms, is stained in tissue and tracheobronchial secretions by methenamine silver, toluidine blue, or Giemsa stain. An immunofluorescent stain using monoclonal antibodies against Pneumocystis is particularly sensitive for detecting the organism in sputum and BAL fluid. The organism identified in 1976 as Legionella pneumophila, the causative agent of Legionnaires’ disease, can be diagnosed by silver impregnation or immunofluorescence staining. The organism also can be grown (with difficulty) on some special media.

Cytologic examination for malignant cells is available for expectorated sputum, specimens obtained by needle aspiration, bronchial washings or brushings obtained with a bronchoscope, and pleural fluid. A specimen can be smeared directly onto a slide (as with a bronchial brushing), subjected to concentration (bronchial washings, pleural fluid), or digested (sputum) prior to being smeared on the slide. The slide then is stained by the Papanicolaou technique, and the cells are examined for findings suggestive or diagnostic of malignancy.

Pathologic examination of tissue sections obtained by biopsy is most useful for diagnosis of malignancy or infection, as well as for a variety of other processes affecting the lungs and pleura. In many circumstances, examination of tissue obtained by biopsy is the gold standard for diagnosis, although even biopsy results can show false-negative findings or yield misleading information.

Tissue obtained by biopsy is routinely stained with hematoxylin and eosin for histologic examination. A wide assortment of other stains is available that more or less specifically stain collagen, elastin, and a variety of microorganisms. Further discussion of the specific techniques and stains can be found in standard pathology textbooks.

Recently, state-of-the-art molecular biology techniques have been applied to respiratory specimens for diagnosis of certain types of respiratory tract infection. When compared with traditional culture methods, the advantages of molecular techniques include rapid detection and specific identification of pathogens, as well as minimizing the hazard to laboratory personnel of exposure to growing pathogens. Techniques based on nucleic acid amplification can be used directly on respiratory specimens for rapid (3–4 hour) detection of the DNA or RNA of some pathogens. For example, the polymerase chain reaction uses specific synthetic oligonucleotide “primer” sequences and DNA polymerase to amplify DNA unique to a specific organism. If the particular target DNA sequence is present, even if only from a single organism, sequential amplification allows production of millions of copies that can be detected by gel electrophoresis. This technique can be applied to samples such as sputum and BAL, providing an exquisitely sensitive test for identifying organisms such as mycobacteria, P. jiroveci, and cytomegalovirus. In addition, oligonucleide hybridization probes allow rapid identification of organisms that have been cultured from clinical specimens. These newer molecular techniques are becoming more readily available and are likely to see increasing clinical use over time.

Assessment on a Functional Level

Pulmonary evaluation on a macroscopic or microscopic level aims at a diagnosis of lung disease, but neither can determine the extent to which normal lung functions are impaired. This final aspect of evaluation adds an important dimension to overall patient assessment because it reflects how much the disease may limit daily activities. The two most common methods for determining a patient’s functional status are pulmonary function testing and evaluation of gas exchange (using either arterial blood gases or pulse oximetry). In addition, a variety of measurements taken during exercise can help determine how much exercise a patient can perform and what factors contribute to any limitation of exercise. Many other types of functional studies are useful for clinical or research purposes, but they are not discussed in this chapter.

Pulmonary Function Tests

Pulmonary function testing provides an objective method for assessing functional changes in a patient with known or suspected lung disease. With the results of tests that are widely available, the physician can answer several questions: (1) Does the patient have significant lung disease sufficient to cause respiratory impairment and account for his or her symptoms? (2) What functional pattern of lung disease does the patient have—restrictive or obstructive disease?

In addition, serial evaluation of pulmonary function allows the physician to quantify any improvement or deterioration in a patient’s functional status. Information obtained from such objective evaluation may be essential in deciding when to treat a patient with lung disease and in assessing whether a patient has responded to therapy. Preoperative evaluation of patients can be useful in predicting which patients are likely to have significant postoperative respiratory problems and which are likely to have adequate pulmonary function after lung resection.

Three main categories of information can be obtained with routine pulmonary function testing:

1. Lung volumes, which provide a measurement of the size of the various compartments within the lung

2. Flow rates, which measure maximal flow within the airways

3. Diffusing capacity, which indicates how readily gas transfer occurs from the alveolus to pulmonary capillary blood

Before examining how these tests indicate what type of functional lung disease a patient has, we briefly describe the tests themselves and how they are performed.

Lung Volumes

Although the lung can be subdivided into compartments in different ways, four volumes are particularly important (Fig. 3-15):

Figure 3-15 Subcompartments of lung (lung volumes). Right, Lung volumes are labeled on spirographic tracing. Left, Block diagrams show two ways in which total lung capacity can be subdivided. ERV = Expiratory reserve volume; FRC = functional residual capacity; IC = inspiratory capacity; RV = residual volume; TLC = total lung capacity; VC = vital capacity; V_T = tidal volume.

1. Total lung capacity (TLC): total volume of gas within the lungs after a maximal inspiration

2. Residual volume (RV): volume of gas remaining within the lungs after a maximal expiration

3. Vital capacity (VC): volume of gas expired when going from TLC to RV

4. Functional residual capacity (FRC): volume of gas within the lungs at the resting state—that is, at the end of expiration during the normal tidal breathing pattern

VC can be measured by having the patient exhale into a spirometer from TLC down to RV. By definition, the volume expired in this manner is the VC. However, because RV, FRC, and TLC all include the amount of gas left within the lungs even after a maximal expiration, these volumes cannot be determined simply by having the patient breathe into a spirometer. To quantify these volumes, a variety of methods can measure one of the three volumes, and the other two can then be calculated or derived from the spirometric tracing. Two methods are described here:

1. Dilution tests: A known volume of an inert gas (usually helium) at a known concentration is inhaled into the lungs. This gas is diluted by the volume of gas already present within the lungs, and the concentration of expired gas (relative to inspired) therefore reflects the initial volume of gas in the lungs.

2. Body plethysmography: The patient, sitting inside an airtight box, performs a maneuver that causes expansion and compression of gas within the thorax. By measuring volume and pressure changes and by applying Boyle’s law, the volume of gas in the thorax can be calculated.

Lung volumes are determined by spirometry and either gas dilution or body plethysmography.

In many circumstances, dilution methods are adequate for determining lung volumes. However, for patients who have air spaces within the lung that do not communicate with the bronchial tree (e.g., bullae), the inhaled gas is not diluted in these noncommunicating areas, and the measured lung volumes determined by dilution methods are falsely low. In such situations, body plethysmography gives a more accurate reflection of intrathoracic gas volume inasmuch as it does not depend on ready communication of all peripheral air spaces with the bronchial tree.

Flow Rates

Measurement of flow rates on routine pulmonary function testing involves assessing airflow during maximal forced expiration—that is, with the patient blowing out as hard and as fast as possible from TLC down to RV. The volume expired during the first second of such a forced expiratory maneuver is called the forced expiratory volume in 1 second (FEV₁) (Fig. 3-16). When pulmonary function tests are interpreted, FEV₁ is routinely compared with VC, or with VC specifically measured during the forced expiratory maneuver, called the forced vital capacity (FVC). In interpreting flow rates, the ratio between these two measurements (FEV₁/VC or FEV₁/FVC) is the most important number used to determine the presence of obstruction to airflow. Another parameter often calculated from the forced expiratory maneuver is the maximal midexpiratory flow rate (MMFR), which is the rate of airflow during the middle one half of the expiration (between 25% and 75% of the volume expired during the FVC). MMFR is frequently called the forced expiratory flow (FEF) between 25% and 75% of vital capacity (FEF_25%–75%). The MMFR or FEF_25%–75% is a relatively sensitive index of airflow obstruction and may be abnormal when the FEV₁/FVC ratio is still preserved.

Figure 3-16 Forced expiratory spirogram. Volume is plotted against time while patient breathes out as hard and fast as possible from total lung capacity (TLC) to residual volume (RV). FEV₁ = Forced expiratory volume in 1 second; FVC = forced vital capacity; MMFR = maximal mid-expiratory flow rate (also called forced expiratory flow from 25%–75% [FEF_25%–75%]); VC = vital capacity.

Maximal expiratory airflow is assessed by the FEV₁/FVC (or FEV₁/VC) ratio and MMFR (FEF_25%–75%).

Diffusing Capacity

The diffusing capacity is a measurement of the rate of transfer of gas from the alveolus to hemoglobin within a capillary, measured in relation to the driving pressure of the gas across the alveolar-capillary membrane. Small concentrations of carbon monoxide are generally used for this purpose. Carbon monoxide combines readily with hemoglobin, and the rate of transfer of gas from the alveolus to the capillary depends on movement through the alveolar-capillary membrane and the amount of hemoglobin available for binding the carbon monoxide.

The measurement obtained during a diffusing capacity test is primarily dependent on the number of functioning alveolar-capillary units—that is, the surface area available for gas exchange—and the volume of blood (hemoglobin) in the pulmonary capillaries available to bind carbon monoxide. Despite the name, as the test is performed in clinical practice, the influence of the thickness of the alveolar-capillary membrane on the measured value is actually minimal. Since the uptake of carbon monoxide by hemoglobin is dependent on the hemoglobin concentration in the blood, patients with anemia may have a depressed diffusing capacity measurement even if the lungs are normal. Therefore, the observed value is generally corrected for the patient’s hemoglobin level.

In practice, the diffusing capacity is commonly decreased in three categories of disease in which surface area for gas exchange is lost, pulmonary capillary blood volume is decreased, or both: (1) emphysema, (2) interstitial lung disease, and (3) pulmonary vascular disease. In disorders that affect only the airways and not pulmonary parenchymal tissue (e.g., asthma, chronic bronchitis), diffusing capacity is generally preserved. On the other hand, the diffusing capacity may be elevated in cases of recent intrapulmonary hemorrhage as a result of uptake of carbon monoxide by hemoglobin in the erythrocytes within the alveolar spaces.

Diffusing capacity of carbon monoxide depends largely on the surface area for gas exchange and the pulmonary capillary blood volume.

Interpretation of Normality in Pulmonary Function Testing

Interpretation of pulmonary function tests necessarily involves a qualitative judgment about normality or abnormality on the basis of quantitative data obtained from these tests. To arrive at a relatively objective judgment, the patient’s values are compared with normal standards established for each test, based on measurements in large numbers of normal nonsmoking control subjects. Separate regression equations for men and women have been constructed to fit the data obtained from these normal control subjects. Separate race/ethnicity-specific equations are available because of slight differences in pulmonary function in normal individuals of different races and ethnicities. A “normal” or predicted value for a test in a given patient can be determined by inputting the patient’s age and height into the appropriate regression equation.

The standards for determining what constitutes the “lower limits of normal” for a particular test vary among laboratories. Most laboratories now consider values below the bottom 5th percentile of a normal reference group (also called the “95% confidence interval”) to be abnormal, whereas others consider an observed value to be abnormal if it is less than 80% of the predicted value. No matter which criteria are used, all the data must be considered to determine whether certain patterns are consistently present. Interpretation of any test in isolation, with the assumption that a patient with a value of 79% has lung disease, but a patient with a value of 81% is disease free, is obviously dangerous.

As a general rule, the normal FEV₁/VC or FEV₁/FVC ratio is 0.70 or greater. An individual without lung disease should, during the first second of a maximal exhalation, be able to exhale at least 70% of the total volume exhaled. However, because the normal ratio can decrease with age, the actual value ideally should be considered abnormal if it is less than the 95% confidence interval for that patient’s age.

Patterns of Pulmonary Function Impairment

In the analysis of pulmonary function tests, abnormalities usually are categorized as one of two patterns (or a combination of the two): (1) an obstructive pattern, characterized mainly by obstruction to airflow, and (2) a restrictive pattern, with evidence of decreased lung volumes but no airflow obstruction.

An obstructive pattern, as seen in patients with asthma, chronic bronchitis, and emphysema, consists of a decrease in rates of expiratory airflow and usually manifests as a decrease in MMFR and FEV₁/FVC ratio (Fig. 3-17). There is generally a high RV and an increased RV/TLC ratio, indicating air trapping due to closure of airways during forced expiration (Fig. 3-18). Hyperinflation, reflected by an increased TLC, is often found, particularly in patients with emphysema. Diffusing capacity tends to be decreased in patients who have loss of alveolar-capillary bed (as seen in emphysema) but not in those without loss of available surface area for gas exchange (as in chronic bronchitis and asthma).

Figure 3-17 Forced expiratory spirograms in normal individual and patient with airflow obstruction. Note prolonged expiration and changes in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV₁) in patient with obstructive disease. MMFR = Maximal mid-expiratory flow rate.

Figure 3-18 Diagram of lung volumes (total lung capacity [TLC] and subcompartments vital capacity [VC] and residual volume [RV]) in normal individual and patients with obstructive and restrictive disease.

The hallmark of restrictive disease is a reduction in lung volumes, whereas expiratory airflow is normal (see Fig. 3-18). Therefore, TLC, RV, VC, and FRC all tend to be reduced, whereas MMFR and FEV₁/FVC are preserved. In some patients with significant loss of volume resulting from restrictive disease, MMFR is decreased because less volume is available to generate a high flow rate. Interpreting a low MMFR in the face of significant restrictive disease is difficult unless MMFR is clearly decreased out of proportion to the decrease in lung volumes.

Patterns of impairment:

1. Obstructive: diminished rates of expiratory airflow (↓ FEV₁/FVC, ↓ MMFR)

2. Restrictive: diminished lung volumes (especially ↓ TLC) and preserved expiratory airflow

A wide variety of parenchymal, pleural, neuromuscular, and chest wall diseases can demonstrate a restrictive pattern. Certain clues are useful in distinguishing among these causes of restriction. For example, a decrease in the diffusing capacity for carbon monoxide suggests loss of alveolar-capillary units and points toward interstitial disease as the cause of the restrictive pattern. The finding of a relatively high RV can indicate either expiratory muscle weakness or a chest wall abnormality that makes the thoracic cage particularly stiff (noncompliant) at low volumes.

Although lung diseases often occur with one or the other of these patterns, a mixed picture of obstructive and restrictive disease can be present, making interpretation of the tests much more complex. These tests do not directly reflect a patient’s overall capability for O₂ and CO₂ exchange, which is assessed by measurement of arterial blood gases.

A simplified guide to the interpretation of pulmonary function tests is presented along with several sample problems in Appendix B.