Section 1: Diagnosis of Respiratory Disorders

INTRODUCTION

The majority of diseases of the respiratory system present with cough and/or dyspnea and fall into one of three major categories: (1) obstructive; (2) restrictive; and (3) vascular diseases. Obstructive pathophysiology is most common and primarily results from airway diseases, such as asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, and bronchiolitis. Diseases resulting in restrictive pathophysiology include parenchymal lung diseases, abnormalities of the chest wall and pleura, and neuromuscular disease. Pulmonary embolism, pulmonary hypertension, and pulmonary venoocclusive disease are examples of disorders of the pulmonary vasculature. Although many specific diseases fall into these major categories, both infective and neoplastic processes can affect the respiratory system and result in myriad pathologic findings, including those listed in the three categories above (Table 284-1).

Disorders can also be grouped according to gas exchange abnormalities, including hypoxemia, hypercarbia, or combined impairment; however, many respiratory disorders do not manifest as gas exchange abnormalities.

As with the evaluation of most patients, the approach to a patient with a respiratory system disorder begins with a thorough history and a focused physical examination. Many patients will subsequently undergo pulmonary function testing, chest imaging, blood and sputum analysis, a variety of serologic or microbiologic studies, and diagnostic procedures, such as bronchoscopy. This stepwise approach is discussed in detail below.

HISTORY

Dyspnea and Cough

The cardinal symptoms of respiratory disease are dyspnea and cough (Chaps. 37 and 38). Dyspnea has many causes, some of which are not predominantly due to lung pathology. The words a patient uses to describe shortness of breath can suggest certain etiologies for dyspnea. Patients with obstructive lung disease often complain of “chest tightness” or “inability to get a deep breath,” whereas patients with congestive heart failure more commonly report “air hunger” or a sense of suffocation.

The tempo of onset and the duration of a patient’s dyspnea are likewise helpful in determining the etiology. Acute shortness of breath is usually associated with sudden physiologic changes, such as acute airway narrowing (e.g., laryngeal edema, bronchospasm, or mucus plugging), acute hypoxemia (e.g., pulmonary edema, pneumonia, or pulmonary embolism), or sudden changes in the work of breathing (e.g., pneumothorax). Patients with COPD and idiopathic pulmonary fibrosis (IPF) experience a gradual progression of dyspnea on exertion, punctuated by acute exacerbations of shortness of breath. In contrast, most asthmatics do not have daily symptoms, but experience intermittent episodes of dyspnea, cough, and chest tightness that are usually associated with specific triggers, such as an upper respiratory tract infection or exposure to allergens.

Specific questioning should focus on factors that incite dyspnea as well as on any intervention that helps resolve the patient’s shortness of breath. Asthma is commonly exacerbated by specific triggers, although this can also be true of COPD. Many patients with lung disease report dyspnea on exertion. Determining the degree of activity that results in shortness of breath gives the clinician a gauge of the patient’s degree of disability. Many patients adapt their level of activity to accommodate progressive limitation. For this reason, it is important, particularly in older patients, to delineate the activities in which they engage and how these activities have changed over time. Dyspnea on exertion is often an early symptom of underlying lung or heart disease and warrants a thorough evaluation.

For cough, the clinician should inquire about the duration of the cough, whether or not it is associated with sputum production, and any specific triggers that induce it. Acute cough productive of phlegm is often a symptom of infection of the respiratory system, including processes affecting the upper airway (e.g., sinusitis, tracheitis), the lower airways (e.g., bronchitis, bronchiectasis), and the lung parenchyma (e.g., pneumonia). Both the quantity and quality of the sputum, including whether it is blood-streaked or frankly bloody, should be determined. Hemoptysis warrants urgent evaluation as delineated in Chap. 39.

Chronic cough (defined as that persisting for >8 weeks) is commonly associated with obstructive lung diseases, particularly asthma, COPD, and chronic bronchiectasis, as well as “nonrespiratory” diseases, such as gastroesophageal reflux and postnasal drip. Diffuse parenchymal lung diseases, including IPF, frequently present as a persistent, nonproductive cough. All causes of cough are not respiratory in origin, and assessment should encompass a broad differential, including cardiac and gastrointestinal diseases as well as psychogenic causes.

Additional Symptoms

Patients with respiratory disease may report wheezing, which is suggestive of airways disease, particularly asthma. Hemoptysis can be a symptom of a variety of lung diseases, including infections of the respiratory tract, bronchogenic carcinoma, and pulmonary embolism. In addition, chest pain or discomfort can be respiratory in origin. As the lung parenchyma is not innervated with pain fibers, pain in the chest from respiratory disorders usually results from either diseases of the parietal pleura (e.g., pneumothorax) or pulmonary vascular diseases (e.g., pulmonary hypertension). As many diseases of the lung can result in strain on the right side of the heart, patients may also present with symptoms of cor pulmonale, including abdominal bloating or distention and pedal edema (Chap. 257).

Additional History

A thorough social history is an essential component of the evaluation of patients with respiratory disease. All patients should be asked about current or previous cigarette smoking, as this exposure is associated with many diseases of the respiratory system, including COPD, bronchogenic lung cancer, and select parenchymal lung diseases (e.g., desquamative interstitial pneumonitis and pulmonary Langerhans cell histiocytosis). For most of these disorders, increased cigarette smoke exposure (i.e., cigarette pack-years) increases the risk of disease. E-cigarette or vaping use can lead to acute or subacute lung injury (i.e., E-cigarette or vaping use-associated lung injury [EVALI]). Secondhand smoke also increases risk for some respiratory disorders, so patients should also be asked about parents, spouses, or housemates who smoke. Possible inhalational exposures at work (e.g., asbestos, silica) or home (e.g., wood smoke, excrement from pet birds) should be explored (Chap. 289). Travel predisposes to certain infections of the respiratory tract, most notably tuberculosis. Potential exposure to fungi is increased in specific geographic regions or climates (e.g., Histoplasma capsulatum), so exposures to these regions should be determined.

Associated symptoms of fever and chills should raise the suspicion of infective etiologies, both pulmonary and systemic. A comprehensive review of systems may suggest rheumatologic or autoimmune disease presenting with respiratory tract manifestations. Questions should focus on joint pain or swelling, rashes, dry eyes, dry mouth, or constitutional symptoms. In addition, carcinomas from a variety of primary sources commonly metastasize to the lung and cause respiratory symptoms. Finally, therapy for other conditions, including both irradiation and medications, can result in diseases of the chest.

Physical Examination

The clinician’s suspicion of respiratory disease often begins with the patient’s vital signs. The respiratory rate is informative, whether elevated (tachypnea) or depressed (hypopnea). In addition, pulse oximetry should be measured, as many patients with respiratory disease have hypoxemia, either at rest or with exertion.

The first step of the physical examination is inspection. Patients with respiratory disease may be in distress and using accessory muscles of respiration to breathe. Severe kyphoscoliosis can result in restrictive pathophysiology. Inability to complete a sentence in conversation is generally a sign of severe impairment and should result in an expedited evaluation of the patient.

Percussion of the chest is used to establish diaphragm excursion and lung size. In the setting of decreased breath sounds, percussion is used to distinguish between pleural effusions (dull to percussion) and pneumothorax (hyper-resonant note).

The role of palpation is limited in the respiratory examination. Palpation can demonstrate subcutaneous air in the setting of barotrauma. It can also be used as an adjunctive assessment to determine whether an area of decreased breath sounds is due to consolidation (increased tactile fremitus) or a pleural effusion (decreased tactile fremitus). To detect unilateral disorders of ventilation, the symmetry and degree of chest wall expansion can be assessed during a deep inspiration by placing one’s thumbs together at the midline over the lower posterior chest while grasping the lateral rib cage.

The majority of the manifestations of respiratory disease present as abnormalities of auscultation. Wheezes are a manifestation of airway obstruction. While most commonly a sign of asthma, peribronchial edema in the setting of congestive heart failure can also result in diffuse wheezes, as can any other process that causes narrowing of small airways. Wheezes can be polyphonic, involving multiple different size airways (e.g., asthma), or monophonic, involving one size airway (e.g., bronchogenic carcinoma). For these reasons, clinicians must take care not to attribute all wheezing to asthma.

Rhonchi are a manifestation of obstruction of medium-sized airways, most often with secretions. In the acute setting, this manifestation may be a sign of viral or bacterial bronchitis. Chronic rhonchi suggest bronchiectasis or COPD. In contrast to expiratory wheezes and rhonchi, stridor is a high-pitched, focal inspiratory wheeze, usually heard over the neck as a manifestation of upper airway obstruction.

Crackles, or rales, are commonly a sign of alveolar disease. Processes that fill the alveoli with fluid may result in crackles, including pulmonary edema and pneumonia. Crackles in pulmonary edema are generally more prominent at the bases. Interestingly, diseases that result in fibrosis of the interstitium (e.g., IPF) also result in crackles that sound like Velcro being ripped apart. Although some clinicians make a distinction between “wet” and “dry” crackles, this distinction has not been shown to be a reliable way to differentiate among etiologies of respiratory disease.

One way to help distinguish between crackles associated with alveolar fluid and those associated with interstitial fibrosis is to assess for egophony. Egophony is the auscultation of the sound “AH” instead of “EEE” when a patient phonates “EEE.” This change in note is due to abnormal sound transmission through consolidated parenchyma and is present in pneumonia but not in IPF. Similarly, areas of alveolar filling have increased whispered pectoriloquy as well as transmission of larger-airway sounds (i.e., bronchial breath sounds in a lung zone where vesicular breath sounds are expected).

The lack or diminution of breath sounds can also help determine the etiology of respiratory disease. Patients with emphysema often have a quiet chest with diffusely decreased breath sounds. A pneumothorax or pleural effusion may present with an area of absent breath sounds.

Other Systems

Pedal edema, if symmetric, may suggest cor pulmonale; if asymmetric, it may be due to deep venous thrombosis and associated pulmonary embolism. Jugular venous distention may also be a sign of volume overload associated with right heart failure. Pulsus paradoxus is an ominous sign in a patient with obstructive lung disease, as it is associated with significant negative intrathoracic (pleural) pressures required for ventilation and impending respiratory failure.

As stated earlier, rheumatologic disease may manifest primarily as lung disease. Owing to this association, particular attention should be paid to joint and skin examination. Clubbing can be found in many lung diseases, including cystic fibrosis, IPF, and lung cancer. Cyanosis is seen in hypoxemic respiratory disorders that result in >5 g of deoxygenated hemoglobin/dL.

DIAGNOSTIC EVALUATION

The sequence of studies is dictated by the clinician’s differential diagnosis, as determined by the history and physical examination. Acute respiratory symptoms are often evaluated with multiple tests performed at the same time in order to diagnose any life-threatening diseases rapidly (e.g., pulmonary embolism or multilobar pneumonia). In contrast, chronic dyspnea and cough can be evaluated in a more protracted, stepwise fashion.

Pulmonary Function Testing

The initial pulmonary function test obtained is spirometry (See also Chap. 286). This study is an effort-dependent test used to assess for obstructive pathophysiology as seen in asthma, COPD, and bronchiectasis (Table 284-1). A diminished-forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) (often defined as <70%) is diagnostic of airflow obstruction. In addition to measuring FEV₁ and FVC, the clinician should examine the flow-volume loop (which is less effort-dependent). A plateau of the inspiratory and expiratory curves suggests large-airway obstruction in extrathoracic and intrathoracic locations, respectively.

Spirometry with symmetric decreases in FEV₁ and FVC warrants further testing, including measurement of lung volumes and the diffusion capacity of the lung for carbon monoxide (Dl_CO). A total lung capacity <80% of the patient’s predicted value defines restrictive pathophysiology. Restriction can result from parenchymal disease, neuromuscular weakness, or chest wall or pleural diseases (Table 284-1). Restriction with impaired gas exchange, as indicated by a decreased Dl_CO, suggests parenchymal lung disease. Additional testing, such as measurements of maximal inspiratory and expiratory pressures, can help diagnose neuromuscular weakness. Normal spirometry, normal lung volumes, and a low Dl_CO should prompt further evaluation for pulmonary vascular disease.

Arterial blood gas testing is often helpful in assessing respiratory disease. Hypoxemia, while usually apparent with pulse oximetry, can be further evaluated with the measurement of arterial PO₂ and the calculation of an alveolar gas and arterial blood oxygen tension difference ([A–a]DO₂). Patients with diseases that cause ventilation-perfusion mismatch or shunt physiology have an increased (A–a)DO₂ at rest. Arterial blood gas testing also allows the measurement of arterial Pco₂. Hypercarbia can accompany disorders of ventilation, as seen in severe airway obstruction (e.g., COPD) or progressive restrictive physiology.

Chest Imaging

Most patients with disease of the respiratory system undergo imaging of the chest as part of the initial evaluation (See Chap. A12). Clinicians should generally begin with ultrasound of the chest or a plain chest radiograph, preferably posterior-anterior and lateral films. Ultrasound is often readily available and can help rapidly diagnose pneumothorax, pleural effusion, and consolidation of lung parenchyma. Chest radiographs give additional detail and can reveal findings including opacities of the parenchyma, blunting of the costophrenic angles, mass lesions, and volume loss. Of note, many diseases of the respiratory system, particularly those of the airways and pulmonary vasculature, are associated with a normal chest radiograph.

CT scan of the chest can also be useful to delineate parenchymal processes, pleural disease, masses or nodules, and large airways. If the test includes administration of intravenous contrast, the pulmonary vasculature can be assessed with particular utility for determination of pulmonary emboli. Intravenous contrast also allows lymph nodes to be examined in greater detail. When coupled with positron emission tomography (PET), lesions of the chest can be assessed for metabolic activity, helping differentiate between malignancy and scar.

FURTHER STUDIES

Depending on the clinician’s suspicion, a variety of other studies may be done. Concern about large-airway lesions may warrant bronchoscopy. This procedure may also be used to sample the alveolar space with bronchoalveolar lavage or to obtain nonsurgical lung biopsies. Blood testing may include assessment for hypercoagulable states in the setting of pulmonary vascular disease, serologic testing for infectious or rheumatologic disease, or assessment of inflammatory markers or leukocyte counts (e.g., eosinophils). Genetic testing is increasingly used for heritable lung diseases such as cystic fibrosis. Sputum evaluation for malignant cells or microorganisms may be appropriate. An echocardiogram to assess right- and left-sided heart function is often obtained. Finally, at times, a surgical lung biopsy is needed to diagnose certain diseases of the respiratory system. All of these studies will be guided by the preceding history, physical examination, pulmonary function testing, and chest imaging.

ACKNOWLEDGEMENT

Patricia Kritek contributed to this chapter in the 20th edition, and some material from that chapter has been retained here.

FURTHER READING

INTRODUCTION

The primary functions of the respiratory system—to oxygenate blood and eliminate carbon dioxide—require virtual contact between blood and fresh air, which facilitates diffusion of respiratory gases between blood and gas. This process occurs in the lung alveoli, where blood flowing through alveolar wall capillaries is separated from alveolar gas by an extremely thin membrane of flattened endothelial and epithelial cells, across which respiratory gases diffuse and equilibrate. Blood flow through the lung is unidirectional via a continuous vascular path along which venous blood absorbs oxygen from and loses CO₂ to inspired gas. The path for airflow, in contrast, reaches a dead end at the alveolar walls; thus, the alveolar space must be ventilated tidally, with inflow of fresh gas and outflow of alveolar gas alternating periodically at the respiratory rate (RR). To provide an enormous alveolar surface area (typically 70 m²) for blood-gas diffusion within the modest volume of a thoracic cavity (typically 7 L), nature has distributed both blood flow and ventilation among millions of tiny alveoli through multigenerational branching of both pulmonary arteries and bronchial airways. Ideally, for the lung to be most efficient in exchanging gas, the fresh gas ventilation of a given alveolus must be matched to its perfusion. However, as a consequence of variations in tube lengths and calibers along these pathways as well as the effects of gravity, tidal pressure fluctuations, and anatomic constraints from the chest wall, the alveoli vary in their relative ventilations and perfusions even in health.

For the respiratory system to succeed in oxygenating blood and eliminating CO₂, it must be able to ventilate the lung tidally and thus to freshen alveolar gas; it must provide for perfusion of the individual alveolus in a manner proportional to its ventilation; and it must allow adequate diffusion of respiratory gases between alveolar gas and capillary blood. Furthermore, it must accommodate several-fold increases in the demand for oxygen uptake or CO₂ elimination imposed by metabolic needs or acid-base derangement. Given these multiple requirements for normal operation, it is not surprising that many diseases disturb respiratory function. This chapter considers in some detail the physiologic determinants of lung ventilation and perfusion, elucidates how the matching distributions of these processes and rapid gas diffusion allow normal gas exchange, and discusses how common diseases derange these normal functions, thereby impairing gas exchange—or at least increasing the work required by the respiratory muscles or heart to maintain adequate respiratory function.

VENTILATION

It is useful to conceptualize the respiratory system as three independently functioning components: the lung, including its airways; the neuromuscular system; and the chest wall, which includes everything that is not lung or active neuromuscular system. Accordingly, the mass of the respiratory muscles is part of the chest wall, while the force these muscles generate is part of the neuromuscular system; the abdomen (especially an obese abdomen) and the heart (especially an enlarged heart) are, for these purposes, part of the chest wall. Each of these three components has mechanical properties that relate to its enclosed volume (or—in the case of the neuromuscular system—the respiratory system volume at which it is operating) and to the rate of change of its volume (i.e., flow). The work of breathing required of the neuromuscular system is the sum of the work due to volume-related mechanical properties and the work from flow-related mechanical properties required to move air throughout the airways to create this volume change.

Volume-Related Mechanical Properties—Statics

Figure 285-1 shows the volume-related properties of each component of the respiratory system. Because of both surface tension at the air-liquid interface between alveolar wall lining fluid and alveolar gas and elastic recoil of the lung tissue itself, the lung requires a positive transmural pressure difference between alveolar gas and its pleural surface to stay inflated; this difference is called the elastic recoil pressure of the lung, and it increases with lung volume. The lung becomes rather stiff at high volumes, so that relatively small volume changes are accompanied by large changes in transpulmonary pressure; in contrast, the lung is compliant at lower volumes, including those at which tidal breathing normally occurs. At zero inflation pressure, even normal lungs retain some air in the alveoli. Because the small peripheral airways are tethered open by outward radial pull from inflated lung parenchyma attached to adventitia, as the lung deflates during exhalation, those small airways are pulled open progressively less, and eventually close, trapping some gas in the alveoli. This effect can be exaggerated with age and especially with obstructive airway diseases, resulting in gas trapping at quite large lung volumes.

The elastic behavior of the passive chest wall (i.e., in the absence of neuromuscular activation) differs markedly from that of the lung. Whereas the lung tends toward full deflation with no distending (transmural) pressure, the chest wall encloses a large volume when pleural pressure equals body surface (atmospheric) pressure. Furthermore, the chest wall is compliant at high enclosed volumes, readily expanding even further in response to increases in transmural pressure. The chest wall also remains compliant at small negative transmural pressures (i.e., when pleural pressure falls slightly below atmospheric pressure), but as the volume enclosed by the chest wall becomes quite small in response to large negative transmural pressures, the passive chest wall becomes stiff due to squeezing together of ribs and intercostal muscles, diaphragm stretch, displacement of abdominal contents, and straining of ligaments and bony articulations. Under normal circumstances, the lung and the passive chest wall enclose essentially the same volume, the only difference being the volumes of the pleural fluid and of the lung parenchyma (normally both quite small in the absence of disease). For this reason and because the lung and chest wall function in mechanical series, the pressure required to displace the passive respiratory system (lungs plus chest wall) at any volume is simply the sum of the elastic recoil pressure of the lungs and the transmural pressure across the chest wall. When plotted against respiratory system volume, this relationship assumes a sigmoid shape, exhibiting stiffness at high lung volumes (imparted by the lung), stiffness at low lung volumes (imparted by the chest wall or sometimes by airway closure), and compliance in the middle range of lung volumes where normal tidal breathing occurs. In addition, a passive resting point of the respiratory system is attained when alveolar gas pressure equals body surface pressure (i.e., when the transrespiratory system pressure is zero). At this volume (called the functional residual capacity [FRC]), the outward recoil of the chest wall is balanced exactly by the inward recoil of the lung. As these recoils are transmitted through the pleural fluid, the lung is pulled both outward and inward simultaneously at FRC, and thus, its pressure falls below atmospheric pressure (typically, −5 cmH₂O).

The normal passive respiratory system would equilibrate at the FRC and remain there were it not for the actions of the respiratory muscles. The inspiratory muscles act on the chest wall to generate the equivalent of positive pressure across the lungs and passive chest wall, while the expiratory muscles generate the equivalent of negative transrespiratory pressure. The maximal pressures these sets of muscles can generate vary with the lung volume at which they operate. This variation is due to length-tension relationships in striated muscle sarcomeres and to changes in mechanical advantage as the angles of insertion change with lung volume (Fig. 285-1). Nonetheless, under normal conditions, the respiratory muscles are substantially “overpowered” for their roles and generate more than adequate force to drive the respiratory system to its stiffness extremes, as determined by the lung (total lung capacity [TLC]) or by chest wall or airway closure (residual volume [RV]); the airway closure always prevents the adult lung from emptying completely under normal circumstances. The excursion between full and minimal lung inflation is called vital capacity (VC; Fig. 285-2) and is readily seen to be the difference between volumes at two unrelated stiffness extremes—one determined by the lung (TLC) and the other by the chest wall or airways (RV). Thus, although VC is easy to measure (see below), it provides little information about the intrinsic properties of the respiratory system. As will become clear, it is much more useful for the clinician to consider TLC and RV individually.

Flow-Related Mechanical Properties—Dynamics

The passive chest wall and active neuromuscular system both exhibit mechanical behaviors related to the rate of change of volume, but these behaviors become quantitatively important only at markedly supraphysiologic breathing frequencies (e.g., during high-frequency mechanical ventilation), and thus will not be addressed here. In contrast, the dynamic airflow properties of the lung substantially affect its ability to ventilate and contribute importantly to the work of breathing, and these properties are often deranged by disease. Understanding dynamic airflow properties is, therefore, worthwhile.

As with the flow of any fluid (gas or liquid) in any tube, maintenance of airflow within the pulmonary airways requires a pressure gradient that falls along the direction of flow, the magnitude of which is determined by the flow rate and the frictional resistance to flow. During quiet tidal breathing, the pressure gradients driving inspiratory or expiratory flow are small owing to the very low frictional resistance of normal pulmonary airways (R_aw, normally <2 cmH₂O/L/s). However, during rapid exhalation, another phenomenon reduces flow below that which would have been expected if frictional resistance were the only impediment to flow. This phenomenon is called dynamic airflow limitation, and it occurs because the bronchial airways through which air is exhaled are collapsible rather than rigid (Fig. 285-3). An important anatomic feature of the structure of the pulmonary airways is their tree like branching. While the individual airways in each successive generation, from most proximal (trachea) to most distal (respiratory bronchioles), are smaller than those of the parent generation, their number increases exponentially such that the summed cross-sectional area of the airways becomes very large toward the lung periphery. Because flow (volume/time) is constant along the airway tree, the velocity of airflow (flow/summed cross-sectional area) is much greater in the central airways than in the peripheral airways. During exhalation, gas leaving the alveoli must, therefore, gain velocity as it proceeds toward the mouth. The energy required for this “convective” acceleration is drawn from the component of gas energy manifested as its local pressure, which reduces intraluminal gas pressure, airway transmural pressure, airway size (Fig. 285-3), and flow. This phenomenon is the Bernoulli effect, the same effect that keeps an airplane airborne, generating a lifting force by decreasing pressure above the curved upper surface of the wing due to acceleration of air flowing over the wing. If an individual attempts to exhale more forcefully, the local velocity increases further and reduces airway size further, resulting in no net increase in flow. Under these circumstances, flow has reached its maximum possible value, or its flow limit. Lungs normally exhibit such dynamic airflow limitation. This limitation can be assessed by spirometry, in which an individual inhales fully to TLC and then forcibly exhales to RV. One useful spirometric measure is the volume of air exhaled during the forced expiratory volume in 1 s (FEV₁), as discussed later. Maximal expiratory flow at any lung volume is determined by gas density, airway cross-section and distensibility, elastic recoil pressure of the lung, and frictional pressure loss to the flow-limiting airway site. Under normal conditions, maximal expiratory flow falls with lung volume (Fig. 285-4), primarily because of the dependence of lung recoil pressure on lung volume (Fig. 285-1). In pulmonary fibrosis, lung recoil pressure is increased at any lung volume, and thus the maximal expiratory flow is elevated when considered in relation to lung volume. Conversely, in emphysema, lung recoil pressure is reduced; this reduction is a principal mechanism by which maximal expiratory flows fall. Diseases that narrow the airway lumen at any transmural pressure (e.g., asthma or chronic bronchitis) or that cause excessive airway collapsibility (e.g., tracheomalacia) also reduce maximal expiratory flow.

The Bernoulli effect also applies during inspiration, but the more negative pleural pressures during inspiration lower the pressure outside of the airways, thereby increasing transmural pressure and promoting airway expansion. Thus, inspiratory airflow limitation seldom occurs due to diffuse pulmonary airway disease. Conversely, extrathoracic airway narrowing (e.g., due to a tracheal adenoma or post-tracheostomy stricture) can lead to inspiratory airflow limitation (Fig. 285-4).

The Work of Breathing

In health, the elastic (volume change-related) and dynamic (flow-related) loads that must be overcome to ventilate the lungs at rest are small, and the work required of the respiratory muscles is minimal. However, the work of breathing can increase considerably due to a metabolic requirement for substantially increased ventilation, an abnormally increased mechanical load, or both. As discussed below, the rate of ventilation is primarily set by the need to eliminate carbon dioxide, and thus, ventilation increases during exercise (sometimes by >20-fold) and during metabolic acidosis as a compensatory response. Naturally, the work rate required to overcome the elasticity of the respiratory system increases with both the depth and the frequency of tidal breaths, while the work required to overcome the dynamic load increases with total ventilation. A modest increase of ventilation is most efficiently achieved by increasing tidal volume but not RR, which is the normal ventilatory response to lower-level exercise. At higher levels of exercise, deep breathing persists, but RR also increases.

The work of breathing also increases when disease reduces the compliance of the respiratory system or increases the resistance to airflow. The former occurs commonly in diseases of the lung parenchyma (interstitial processes or fibrosis, alveolar filling diseases such as pulmonary edema or pneumonia, or substantial lung resection), and the latter occurs in obstructive airway diseases such as asthma, chronic bronchitis, emphysema, and cystic fibrosis. Furthermore, severe airflow obstruction can functionally reduce the compliance of the respiratory system by leading to dynamic hyperinflation. In this scenario, expiratory flows slowed by the obstructive airways disease may be insufficient to allow complete exhalation during the expiratory phase of tidal breathing; as a result, the “functional residual capacity (FRC)” from which the next breath is inhaled is greater than the static FRC. With repetition of incomplete exhalations of each tidal breath, the operating FRC becomes dynamically elevated, sometimes to a level that approaches TLC. At these high lung volumes, the respiratory system is much less compliant than at normal breathing volumes, and thus, the elastic work of each tidal breath is also increased. The dynamic pulmonary hyperinflation that accompanies severe airflow obstruction causes patients to sense difficulty in inhaling—even though the root cause of this pathophysiologic abnormality is expiratory airflow obstruction.

Adequacy of Ventilation

As noted above, the respiratory control system that sets the rate of ventilation responds to chemical signals, including arterial CO₂ and oxygen tensions and blood pH, and to volitional needs, such as the need to inhale deeply before playing a long phrase on the trumpet. Disturbances in ventilation are discussed in Chap. 296. The focus of this chapter is on the relationship between ventilation of the lung and CO₂ elimination.

At the end of each tidal exhalation, the conducting airways are filled with alveolar gas that did not reach the mouth when expiratory flow stopped. During the ensuing inhalation, fresh gas immediately enters the airway tree at the mouth, but the gas first entering the alveoli at the start of inhalation is that same alveolar gas in the conducting airways that had just left the alveoli. Accordingly, fresh gas does not enter the alveoli until the volume of the conducting airways has been inspired. This volume is called the anatomic dead space (V_D). Quiet breathing with tidal volumes smaller than the anatomic dead space introduces no fresh gas into the alveoli at all; only that part of the inspired tidal volume (V_T) that is greater than the V_D introduces fresh gas into the alveoli. The dead space can be further increased functionally if some of the inspired tidal volume is delivered to a part of the lung that receives no pulmonary blood flow and thus cannot contribute to gas exchange (e.g., the portion of the lung distal to a large pulmonary embolus). In this situation, exhaled minute ventilation (V̇_E= V_T × RR) includes a component of dead space ventilation (V̇_D= V_D × RR) and a component of fresh gas alveolar ventilation (V̇_A= [V_T − V_D] × RR). CO₂ elimination from the alveoli is equal to V̇_A times the difference in CO₂ fraction between inspired air (essentially zero) and alveolar gas (typically ~5.6% after correction for humidification of inspired air, corresponding to 40 mmHg). In the steady state, the alveolar fraction of CO₂ is equal to metabolic CO₂ production divided by alveolar ventilation. Because, as discussed below, alveolar and arterial CO₂ tensions are equal, and because the respiratory controller normally strives to maintain arterial Pco₂ (Paco₂) at ~40 mmHg, the adequacy of alveolar ventilation is reflected in Paco₂ If the Paco₂ falls much below 40 mmHg, alveolar hyperventilation is present; if the Paco₂ exceeds 40 mmHg, alveolar hypoventilation is present. Ventilatory failure is characterized by extreme alveolar hypoventilation.

As a consequence of oxygen uptake of alveolar gas into capillary blood, alveolar oxygen tension falls below that of inspired gas. The rate of oxygen uptake (determined by the body’s metabolic oxygen consumption) is related to the average rate of metabolic CO₂ production, and their ratio—the “respiratory quotient” (R = V̇CO₂/V̇O₂)—depends largely on the fuel being metabolized. For a typical American diet, R is usually around 0.85. Together, these phenomena allow the estimation of alveolar oxygen tension, according to the following relationship, known as the alveolar gas equation:

The alveolar gas equation also highlights the influences of inspired oxygen fraction Fio₂ barometric pressure (P_bar), and vapor pressure of water (Ph₂o = 47 mmHg at 37°C) in addition to alveolar ventilation (which sets Paco₂) in determining Pao₂. An implication of the alveolar gas equation is that severe arterial hypoxemia rarely occurs as a pure consequence of alveolar hypoventilation at sea level while an individual is breathing air. The potential for alveolar hypoventilation to induce severe hypoxemia with otherwise normal lungs increases as P_bar falls with increasing altitude.

GAS EXCHANGE

Diffusion

For oxygen to be delivered to the peripheral tissues, it must pass from alveolar gas into alveolar capillary blood by diffusing through alveolar membrane. The aggregate alveolar membrane is highly optimized for this process, with a very large surface area and minimal thickness. Diffusion through the alveolar membrane is so efficient in the human lung that in most circumstances hemoglobin of a red blood cell becomes fully oxygen saturated by the time the cell has traveled just one-third the length of the alveolar capillary. Thus, the uptake of alveolar oxygen is ordinarily limited by the amount of blood transiting the alveolar capillaries rather than by the rapidity with which oxygen can diffuse across the membrane; consequently, oxygen uptake from the lung is said to be “perfusion limited” rather than diffusion limited. CO₂ also equilibrates rapidly across the alveolar membrane. Therefore, the oxygen and CO₂ tensions in capillary blood leaving a normal alveolus are essentially equal to those in alveolar gas. Only in rare circumstances (e.g., at high altitude or in high-performance athletes exerting maximal effort) is oxygen uptake from normal lungs diffusion limited. Diffusion limitation can also occur in interstitial lung disease if substantially thickened alveolar walls remain perfused.

Ventilation/Perfusion Heterogeneity

As noted above, for gas exchange to be most efficient, ventilation to each individual alveolus (among the millions of alveoli) should match perfusion to its accompanying capillaries. Because of the differential effects of gravity on lung mechanics and blood flow throughout the lung and because of differences in airway and vascular architecture among various respiratory paths, there is minor ventilation/perfusion heterogeneity even in the normal lung; however, V̇/Q̇ heterogeneity can be particularly marked in disease. Two extreme examples are (1) ventilation of unperfused lung distal to a pulmonary embolus, in which ventilation of the physiologic dead space is “wasted” in the sense that it does not contribute to gas exchange; and (2) perfusion of nonventilated lung (a “shunt”), which allows venous blood to pass through the lung unaltered. When mixed with fully oxygenated blood leaving other well-ventilated lung units, shunted venous blood disproportionately lowers the mixed arterial Pao₂ as a result of the nonlinear oxygen content versus PO₂ relationship of hemoglobin (Fig. 285-5). Furthermore, the resulting arterial hypoxemia is refractory to supplemental inspired oxygen. The reason is that (1) raising the inspired Fio₂ has no effect on alveolar gas tensions in nonventilated alveoli and (2) while raising inspired Fio₂ increases Paco₂ in ventilated alveoli, the oxygen content of blood exiting ventilated units increases only slightly, as hemoglobin will already have been nearly fully saturated and the solubility of oxygen in plasma is quite small.

A more common occurrence than the two extreme examples given above is a widening of the distribution of ventilation/perfusion ratios; such V̇/Q̇ heterogeneity is a common consequence of lung disease. In this circumstance, perfusion of relatively underventilated alveoli results in the incomplete oxygenation of exiting blood. When mixed with well-oxygenated blood leaving higher V̇/Q̇ regions, this partially reoxygenated blood disproportionately lowers arterial Pao₂, although to a lesser extent than does a similar perfusion fraction of blood leaving regions of pure shunt. In addition, in contrast to shunt regions, inhalation of supplemental oxygen raises the Pao₂ even in relatively underventilated low V̇/Q̇ regions, and so the arterial hypoxemia induced by V̇/Q̇ heterogeneity is typically responsive to oxygen therapy (Fig. 285-5).

In sum, arterial hypoxemia can be caused by substantial reduction of inspired oxygen tension, severe alveolar hypoventilation, perfusion of relatively underventilated (low V̇/Q̇) or completely unventilated (shunt) lung regions, and, in very unusual circumstances, limitation of gas diffusion.

PATHOPHYSIOLOGY

Although many diseases injure the respiratory system, this system responds to injury in relatively few ways. For this reason, the pattern of physiologic abnormalities may or may not provide sufficient information by which to discriminate among conditions.

Figure 285-6 lists abnormalities in pulmonary function testing that are typically found in a number of common respiratory disorders and highlights the simultaneous occurrence of multiple physiologic abnormalities. The coexistence of some of these respiratory disorders results in more complex superposition of these abnormalities. Methods to measure respiratory system function clinically are described later in this chapter.

Ventilatory Restriction due to Increased Elastic Recoil—Example: Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis raises lung recoil at all lung volumes, thereby lowering TLC, FRC, and RV as well as forced vital capacity (FVC). Maximal expiratory flows are also reduced from normal values but are elevated when considered in relation to lung volumes. Increased flow occurs both because the increased lung recoil drives greater maximal flow at any lung volume and because airway diameters are relatively increased due to greater radially outward traction exerted on bronchi by the stiff lung parenchyma. For the same reason, airway resistance is also normal. Destruction of the pulmonary capillaries by the fibrotic process results in a marked reduction in diffusing capacity (see below). Oxygenation is often severely reduced by persistent perfusion of alveolar units that are relatively underventilated due to fibrosis of nearby (and mechanically linked) lung due to those alveolar units already being stretched to their maximum volume with little further increase in volume with inspiration. The flow-volume loop (see below) looks like a miniature version of a normal loop but is shifted toward lower absolute lung volumes and displays maximal expiratory flows that are increased for any given volume over the normal tracing.

Ventilatory Restriction due to Chest Wall Abnormality—Example: Moderate Obesity

As the size of the average American continues to increase, this pattern may become the most common of pulmonary function abnormalities. In moderate obesity, the outward recoil of the chest wall is blunted by the weight of chest wall fat and the space occupied by intraabdominal fat. In this situation, preserved inward recoil of the lung overbalances the reduced outward recoil of the chest wall, and FRC falls. Because respiratory muscle strength and lung recoil remain normal, TLC is typically unchanged (although it may fall in massive obesity) and RV is normal (but may be reduced in massive obesity). Mild hypoxemia may be present due to perfusion of alveolar units that are poorly ventilated because of airway closure in dependent portions of the lung during breathing near the reduced FRC. Flows remain normal, as does the diffusion capacity of the lung for carbon monoxide DLCO unless obstructive sleep apnea (which often accompanies obesity) and associated chronic intermittent hypoxemia have induced pulmonary arterial hypertension, in which case DLCO may be low.

Ventilatory Restriction due to Reduced Muscle Strength—Example: Myasthenia Gravis

In this circumstance, FRC remains normal, as both lung recoil and passive chest wall recoil are normal. However, TLC is low and RV is elevated because respiratory muscle strength is insufficient to push the passive respiratory system fully toward either volume extreme. Caught between the low TLC and the elevated RV, FVC and FEV₁ are reduced as “innocent bystanders.” As airway size and lung vasculature are unaffected, both R_aw and DLCO are normal. Oxygenation is normal unless weakness becomes so severe that the patient has insufficient strength to reopen collapsed alveoli during sighs, with resulting atelectasis.

Airflow Obstruction due to Decreased Airway Diameter—Example: Acute Asthma

During an episode of acute asthma, luminal narrowing due to smooth muscle constriction as well as inflammation and thickening within the small- and medium-sized bronchi raise frictional resistance and reduce airflow. “Scooping” of the flow-volume loop is caused by reduction of airflow, especially at lower lung volumes. Often, airflow obstruction can be reversed by inhalation of β₂-adrenergic agonists acutely or by treatment with inhaled steroids chronically. TLC usually remains normal (although elevated TLC is sometimes seen in long-standing asthma), but FRC may be dynamically elevated. RV is often increased due to exaggerated airway closure at low lung volumes, and this elevation of RV reduces FVC. Because central airways are narrowed, R_aw is usually elevated. Mild arterial hypoxemia is often present due to perfusion of relatively underventilated alveoli distal to obstructed airways (and is responsive to oxygen supplementation), but DLCO is normal or mildly elevated.

Airflow Obstruction due to Decreased Elastic Recoil—Example: Severe Emphysema

Loss of lung elastic recoil in severe emphysema results in pulmonary hyperinflation, of which elevated TLC is the hallmark. FRC is more severely elevated due to both loss of lung elastic recoil and dynamic hyperinflation—the same phenomenon as auto-PEEP (auto–positive end-expiratory pressure), which is the positive end-expiratory alveolar pressure that occurs when a new breath is initiated before the lung volume is allowed to return to FRC. RV is very severely elevated because of airway closure and because exhalation toward RV may take so long that RV cannot be reached before the patient must inhale again. Both FVC and FEV₁ are markedly decreased, the former because of the severe elevation of RV and the latter because loss of lung elastic recoil reduces the pressure driving maximal expiratory flow and also reduces tethering open of small intrapulmonary airways. The flow-volume loop demonstrates marked scooping, with an initial transient spike of flow attributable largely to expulsion of air from collapsing central airways at the onset of forced exhalation. Otherwise, the central airways remain relatively unaffected, so R_aw is normal in “pure” emphysema. Loss of alveolar surface and capillaries in the alveolar walls reduces DL_co; however, because poorly ventilated emphysematous acini are also poorly perfused (due to loss of their capillaries), arterial hypoxemia usually is not seen at rest until emphysema becomes very severe. However, during exercise, Pao₂ may fall precipitously if extensive destruction of the pulmonary vasculature prevents a sufficient increase in cardiac output and mixed venous oxygen content falls substantially. Under these circumstances, any venous admixture through low V̇/Q̇ units has a particularly marked effect in lowering mixed arterial oxygen tension.

FUNCTIONAL MEASUREMENTS

Measurement of Ventilatory Function

LUNG VOLUMES

Figure 285-2 demonstrates a spirometry tracing in which the volume of air entering or exiting the lung is plotted over time. In a slow vital capacity maneuver, the patient inhales from FRC, fully inflating the lungs to TLC, and then exhales slowly to RV; VC, the difference between TLC and RV, represents the maximal excursion of the respiratory system. Spirometry discloses relative volume changes during these maneuvers but cannot reveal the absolute volumes at which they occur. To determine absolute lung volumes, two approaches are commonly used: inert gas dilution and body plethysmography. In the former, a known amount of a nonabsorbable inert gas (usually helium or neon) is inhaled in a single large breath or is rebreathed from a closed circuit; the inert gas is diluted by the gas resident in the lung at the time of inhalation, and its final concentration reveals the volume of resident gas contributing to the dilution. A drawback of this method is that regions of the lung that ventilate poorly (e.g., due to airflow obstruction) may not receive much inspired inert gas and so do not contribute to its dilution. Therefore, inert gas dilution (especially in the single-breath method) often underestimates true lung volumes.

In the second approach, FRC is determined by measuring the compressibility of gas within the chest, which is proportional to the volume of gas being compressed. The patient sits in a body plethysmograph (a chamber usually made of transparent plastic to minimize claustrophobia) and, at the end of a normal tidal breath (i.e., when lung volume is at FRC), is instructed to pant against a closed shutter, thus periodically compressing air within the lung slightly. Pressure fluctuations at the mouth and volume fluctuations within the body box (equal but opposite to those in the chest) are determined, and from these measurements, the thoracic gas volume is calculated by means of Boyle’s law. Once FRC is obtained, TLC and RV are calculated by adding the value for inspiratory capacity and subtracting the value for expiratory reserve volume, respectively (both values having been obtained during spirometry) (Fig. 285-2). The most important determinants of healthy individuals’ lung volumes are height, age, and sex, but there is considerable additional normal variation beyond that accounted for by these parameters. In addition, race influences lung volumes; on average, TLC values are ~12% lower in African Americans and 6% lower in Asian Americans than in Caucasian Americans. In practice, a mean “normal” value is predicted by multivariate regression equations using height, age, and sex, and the patient’s value is divided by the predicted value (often with “race correction” applied) to determine “percent predicted.” For most measures of lung function, 85–115% of the predicted value can be normal; however, in health, the various lung volumes tend to scale together. For example, if one is “normal big” with a TLC 110% of the predicted value, all other lung volumes and spirometry values will also approximate 110% of their respective predicted values. This pattern is particularly helpful in evaluating airflow, as discussed below.

AIR FLOW

As noted above, spirometry plays a key role in lung volume determination. Even more often, spirometry is used to measure airflow, which reflects the dynamic properties of the lung. During an FVC maneuver, the patient inhales to TLC and then exhales rapidly and forcefully to RV; this method ensures that flow limitation has been achieved, so that the precise effort made has little influence on actual flow. The total amount of air exhaled is the FVC, and the amount of air exhaled in the first second is the FEV₁; the FEV₁ is a flow rate, revealing volume change per time. Like lung volumes, an individual’s maximal expiratory flows should be compared with predicted values based on height, age, and sex. While the FEV₁/FVC ratio is typically reduced in airflow obstruction, this condition can also reduce FVC by raising RV, sometimes rendering the FEV₁/FVC ratio “artifactually normal” with the erroneous implication that airflow obstruction is absent. To circumvent this problem, it is useful to compare FEV₁ as a fraction of its predicted value with TLC as a fraction of its predicted value. In health, the results are usually similar. In contrast, even an FEV₁ value that is 95% of its predicted value may actually be relatively low if TLC is 110% of its respective predicted value. In this case, airflow obstruction may be present, despite the “normal” value for FEV₁.

The relationships among volume, flow, and time during spirometry are best displayed in two plots—the spirogram (volume vs time) and the flow-volume loop (flow vs volume) (Fig. 285-4). In conditions that cause airflow obstruction, the site of obstruction is sometimes correlated with the shape of the flow-volume loop. In diseases that cause lower airway obstruction, such as asthma and emphysema, flows decrease more rapidly with declining lung volumes, leading to a characteristic scooping of the flow-volume loop. In contrast, fixed upper-airway obstruction typically leads to inspiratory and/or expiratory flow plateaus (Fig. 285-4).

AIRWAYS RESISTANCE

The total resistance of the pulmonary and upper airways is measured in the same body plethysmograph used to measure FRC. The patient is asked once again to pant, but this time against a closed and then opened shutter. Panting against the closed shutter reveals the thoracic gas volume as described above. When the shutter is opened, flow is directed to and from the body box, so that volume fluctuations in the box reveal the extent of thoracic gas compression, which in turn reveals the pressure fluctuations driving flow. Simultaneous measurement of flow allows the calculation of lung resistance (as flow divided by pressure). In health, R_aw is very low (<2 cmH₂O/L/s), and half of the detected resistance resides within the upper airway. In the lung, most resistance originates in the central airways. For this reason, airways resistance measurement tends to be insensitive to peripheral airflow obstruction.

RESPIRATORY MUSCLE STRENGTH

To measure respiratory muscle strength, the patient is instructed to exhale or inhale with maximal effort against a closed shutter while pressure is monitored at the mouth. Pressures >±60 cmH₂O at FRC are considered adequate and make it unlikely that respiratory muscle weakness accounts for any other resting ventilatory dysfunction that is identified.

Measurement of Gas Exchange

DIFFUSING CAPACITY (DLCO)

This test uses a small (and safe) amount of carbon monoxide (CO) to measure gas exchange across the alveolar membrane during a 10-s breath hold. CO in exhaled breath is analyzed to determine the quantity of CO crossing the alveolar membrane and combining with hemoglobin in red blood cells. This “single-breath diffusing capacity” (DLCO) value increases with the surface area available for diffusion and the amount of hemoglobin within the capillaries, and it varies inversely with alveolar membrane thickness. Thus, DLCO decreases in diseases that thicken or destroy alveolar membranes (e.g., pulmonary fibrosis, emphysema), curtail the pulmonary vasculature (e.g., pulmonary hypertension), or reduce alveolar capillary hemoglobin (e.g., anemia). Single-breath diffusing capacity may be elevated in acute congestive heart failure, asthma, polycythemia, and pulmonary hemorrhage.

Arterial Blood Gases

The effectiveness of gas exchange can be assessed by measuring the partial pressures of oxygen and CO₂ in a sample of blood obtained by arterial puncture. The oxygen content of blood (CaO₂) depends on arterial saturation (%O₂Sat), which is set by Pao₂ pH, and Paco₂ according to the oxyhemoglobin dissociation curve. CaO₂ can also be measured by oximetry (see below):

If hemoglobin saturation alone needs to be determined, this task can be accomplished noninvasively with pulse oximetry.

ACKNOWLEDGMENT

The authors wish to acknowledge the contributions of Drs. Steven E. Weinberger and Irene M. Rosen to this chapter in previous editions.

FURTHER READING

INTRODUCTION

Diagnostic procedures in respiratory disease encompass a wide array of invasive and noninvasive modalities. Methods for acquiring diagnostic specimens are described in this chapter, as are the various imaging modalities at hand. Pulmonary function tests and measurements of gas exchange are described in Chap. 284.

BEDSIDE PLEURAL PROCEDURES

THORACENTESIS

Thoracentesis, also known as pleurocentesis, refers to percutaneous aspiration of fluid from the pleural space. The right and left pleural spaces do not normally communicate with each other, and either can be directly accessed between the thoracic ribs. The current standard of care entails using point-of-care ultrasonography to mark the site of needle puncture; this reduces the risks of “dry tap” as well as complications such as pneumothorax. Beside palliation of symptoms associated with pleural effusion (most commonly dyspnea), thoracentesis may be performed for diagnostic purposes. The range of hematologic, biochemical, microbiologic, and cytologic pleural fluid studies has largely remained unchanged over the past few decades, as has the widespread adoption of Light’s criteria for distinguishing exudates from transudates that were described in 1972. However, newer assays such as mesothelin-1 testing for neoplastic diseases (chiefly mesothelioma) have also become available more recently. More details on pleural fluid testing are described in Chap. 294.

CLOSED PLEURAL BIOPSY

Closed pleural biopsy involves percutaneous sampling of the parietal pleural lining. This procedure can be performed either “blindly” (typically with an Abrams needle) or by using imaging guidance such as CT or ultrasound. Closed pleural biopsy without ultrasound guidance is highly sensitive for pleural tuberculosis, owing to the diffuse pleural involvement that is typically seen in those cases.

Image-guided closed pleural biopsy is most helpful in case of focal pleural abnormalities such as pleural nodules, which are virtually pathognomonic of malignant involvement. Limited studies have shown high diagnostic yields of around 80–90% with this modality, but patient selection is key as the diagnostic performance may be considerably lower in the absence of a specific pleural abnormality that could be visualized. Between CT and ultrasound imaging, only ultrasound is typically performed in real-time during the act of obtaining the biopsy.

THORACIC SURGICAL PROCEDURES

THORACOSCOPY AND THORACOTOMY

Thoracoscopy and thoracotomy encompass a spectrum of surgical procedures that involve accessing and operating within the pleural space, either via one or more small entry ports using thoracoscopic tools or via larger incisions as in thoracotomy (Fig. 286-1). Thoracoscopy varies in its scope considerably. An interventional pulmonologist typically performs a pleuroscopy (also known as medical thoracoscopy) and accesses the pleural space through a single port for parietal pleural biopsy or for limited therapeutic purposes such as minor lysis of adhesions, thoracoscopic pleurodesis, or indwelling pleural catheter placement. This procedure can usually be performed safely under conscious sedation. On the other hand, video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracoscopic surgery (RATS) represent more invasive procedures but with more controlled environments entailing general anesthesia with single-lung ventilation, creation of multiple entry ports, and several additional diagnostic and therapeutic possibilities including, but not limited to, lung biopsy, lymph node sampling, lobectomy, decortication, and creation of a pericardial window. Open thoracotomy uses wider incisions and more conventional surgical techniques for performing all of the above as well as additional tasks such as creation of a Clagett window for chronic bronchopleural fistula with empyema.

MEDIASTINOSCOPY AND MEDIASTINOTOMY

Surgical access to the mediastinum, either through a small port (mediastinoscopy) or a wider incision (mediastinotomy), enables diagnostic sampling of mediastinal structures such as mediastinal lymph nodes as part of lung cancer staging. With the advent of endoscopic needle-based techniques (see below), surgery is no longer considered the first-line option for diagnostic lymph node sampling but is recommended in cases of negative needle-based sampling where suspicion for malignant nodal involvement remains sufficiently high.

BRONCHOSCOPY

Bronchoscopy, which entails passing a tube with a lighted camera inside the lower respiratory tract, includes flexible and rigid bronchoscopy (termed after the physical properties of each bronchoscope). Flexible bronchoscopy is by far the more commonly used form and enables access to more distal parts of the respiratory tract. The rigid bronchoscope, although limited to the central airways, has the added advantage of providing a secure airway for ventilation; artificial breaths can then be administered through the scope itself as part of a closed circuit or through open jet ventilation. The rigid bronchoscope also provides a conduit for diagnostic or therapeutic instruments to be passed freely, rather than through the relatively constrained working channel of a flexible bronchoscope. When bronchoscopy is limited to diagnostic indications, the rigid bronchoscope is seldom used except on occasion as a precautionary measure for anticipated severe bleeding where having a more secure airway might be particularly advantageous (e.g., in transbronchial cryobiopsy). Different types of diagnostic bronchoscopic procedures are described below.

Bronchoalveolar Lavage

Bronchoalveolar lavage (BAL) is the gold standard method for obtaining respiratory secretions for hematologic, biochemical, microbiological, and/or cytologic analyses. It avoids the risk of salivary contamination, which may be seen in a sputum specimen, and is particularly useful when sputum cannot be obtained or when sampling of a specific pulmonary lobe or segment is desired. After wedging the bronchoscope in a distal airway in order to prevent fluid escape around the scope, sterile saline or distilled water is instilled through the scope’s working channel (typically in one to three aliquots of approximately 50 mL each). Immediately thereafter, suction is applied to aspirate as much of the fluid as possible. This allows sampling of distal airways and lung parenchyma—areas not directly viewable or accessible. If there is concern for alveolar hemorrhage, serial BALs from the same site may show rising red blood cell counts and even visibly bloodier returns with subsequent lavages.

Brushing and Endobronchial Biopsy

Bronchoscopic brushing is a minimally invasive sampling technique that can be used to sample the mucosal biofilm for microbiologic analyses as well as the bronchial epithelial layer for cytologic analyses. Endobronchial biopsy allows sampling of abnormal bronchial mucosa and submucosa for histopathologic analysis (as may be indicated in cases of endobronchial amyloidosis or sarcoidosis, for example). Among cigarette smokers with one or more lung nodules and a nondiagnostic bronchoscopy, bronchial brushings can be used with a commercially available classifier that estimates lung cancer probability based on a gene expression signature. Patients with intermediate pretest probability who end up with low posttest probability can more confidently opt for imaging surveillance, thus avoiding further invasive testing and related complications.

Transbronchial Biopsy Including Cryobiopsy

Transbronchial biopsy involves removing a piece of alveolated lung tissue by passing a sampling tool into the alveolar space. The most commonly employed biopsy tool is flexible forceps, typically 2.0 mm or 2.8 mm in caliber. When a specific pulmonary lesion such as a lung nodule is being biopsied, various imaging and navigation tools (described below) may be used to help guide the site of forceps biopsy. When random sampling of the lung parenchyma is desired, e.g., to assess for posttransplant lung rejection, either fluoroscopic guidance or tactile feedback is commonly used to position the forceps in the subpleural lung parenchyma. Limited data point to three biopsy samples being adequate for optimizing sensitivity in case of malignant lung nodules. On the other hand, at least five distinct pieces of alveolated lung tissue are needed for formal diagnosis of acute cellular rejection among lung transplant recipients per current recommendations. An increasingly popular biopsy tool is the cryoprobe, a flexible catheter with a blunt tip that delivers liquid nitrogen or carbon dioxide over a few seconds to freeze a portion of lung parenchyma and make it adhere to the probe itself. Before the tissue can thaw and detach, the probe is pulled back (typically along with the bronchoscope itself), and a frozen piece of lung tissue is removed alongside. Cryobiopsy has a higher diagnostic yield than forceps biopsy for diffuse parenchymal illnesses such as idiopathic pulmonary fibrosis but comes with a higher risk of major bleeding and pneumothorax.

Transbronchial Needle Aspiration

Transbronchial needle aspiration (TBNA) involves using a hollow-bore needle for obtaining aspirated specimens. This may be accompanied by suction or simply rely on capillary action, with data not pointing to suction impacting diagnostic sensitivity. TBNA has diagnostic sensitivity superior to that of transbronchial biopsy for malignant peripheral nodules. This makes intuitive sense given that the lesion may lie extraluminally and require traversing the airway wall, which only the needle may be able to accomplish. Furthermore, combining TBNA with conventional transbronchial biopsy appears to increase pooled diagnostic sensitivity.

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration

Endobronchial ultrasound (EBUS) and EBUS-guided transbronchial needle aspiration (EBUS-TBNA) represent a major advance in diagnostic bronchoscopy over the turn of the twentieth century, largely replacing surgical methods for lymph node sampling. EBUS-TBNA involves using a specialized flexible bronchoscope that simultaneously operates a video camera and a convex ultrasound probe (which is installed at its distal end). Under real-time ultrasonographic visualization, the aspiration needle is inserted through the airway wall into the mediastinal target and the aspirate is sent for microbiologic or cytologic analyses as indicated (Fig. 286-2). Newer variants of this technique involve the use of core needles or mini-forceps, providing tissue specimens rather than aspirates that can be sent for histopathologic analysis. EBUS-TBNA has a sensitivity of approximately 90% for epithelial malignancies and approximately 70% for lymphoma (higher for detecting cases of lymphoma recurrence than for de novo lymphoma). For sarcoidosis, estimates point to a sensitivity of at least 80% (higher if combined with endobronchial and transbronchial biopsies). EBUS-TBNA has been shown to provide adequate amounts of material to provide ancillary testing in cases of malignancy, such as immunostaining or genetic testing. A related needle-based technique, also using ultrasound guidance, involves sampling mediastinal structures through the esophagus, which can be a useful adjunct to EBUS-TBNA as it may provide better access to certain mediastinal lymph node stations. The combined sensitivity of these two techniques is slightly higher compared to either one alone. Esophageal sampling can be accomplished either by inserting the same EBUS bronchoscope through the esophagus or by using the standard endoscope used by gastroenterologists for endoscopic ultrasound (EUS).

At many centers, EBUS-TBNA is accompanied by rapid on-site cytologic evaluation (ROSE), wherein a portion of the aspirated specimen is immediately examined by a cytotechnologist or pathologist using rapid staining. This rapid assessment, while often inadequate for a definitive final diagnosis, can be helpful in establishing adequacy of sampled material by providing the bronchoscopist with real-time feedback on whether additional sampling is advisable.

The optimal way to process samples obtained via EBUS-TBNA is unknown. Some centers practice the tissue coagulum clot method, in which multiple aspirates are emptied onto a single piece of filter paper to form a clot that can help with preparation of a cell block. Other centers simply use the residue from spun specimens for this purpose. There is no conclusive evidence that one technique is superior to the other, but this question has not been well studied to date.

Guided Peripheral Bronchoscopy

Guided peripheral bronchoscopy involves the use of advanced tools to aid with one or more of three tasks involved in successful bronchoscopic sampling of peripherally located lesions, such as lung nodules (see below). Various tools are available to help the bronchoscopist accomplish these tasks (Fig. 286-3).

• (A) Navigating to the appropriate lobe/segment/subsegment: Electromagnetic navigational bronchoscopy (which involves GPS-like feedback as the bronchoscope is advanced toward the target) and virtual bronchoscopy (which overlays live endoscopic images onto a CT-derived virtual bronchoscopic map) can help with successful navigation through the airways. Shape-sensing technology, used as part of one robotic bronchoscopy platform (see below), also aims to achieve the same purpose.

• (B) The aforementioned technologies can also help localize a lesion, although they are limited by relying on previously acquired CT images that may or may not accurately represent precisely where the lesion is currently located in a three-dimensional space. Radial EBUS uses a thin ultrasound-tipped catheter that can be passed through the bronchoscope’s working channel all the way to the lung periphery. This provides real-time images of structures beyond airway walls. A concentric image of the target, indicating a lesion with the airway going through its center, is associated with a high diagnostic yield. Alternatively, fluoroscopic imaging can be used to recalibrate the precise target location on navigational bronchoscopic platforms, potentially improving localization as well. Cone-beam CT, which is a distilled version of CT imaging that has been used intra-procedurally in multiple other fields such as interventional radiology, can be used for confirmation of optimal tool-in-lesion (with the patient undergoing a breath hold) prior to sampling.

• (C) The tools available for peripheral sampling include biopsy forceps, brushes, and aspiration needles as described above, with TBNA having the highest diagnostic sensitivity for discrete malignant lesions. Evidence for use of cryobiopsy for sampling discrete lesions in the lung periphery is currently limited. Recent innovations also include steerable sampling tools, which hold promise for more optimal sampling of the target lesion.

Robotic Bronchoscopy

In 2018, the US Food and Drug Administration (FDA) approved two robotic bronchoscopy platforms for commercial use. These platforms offer improved bronchoscope stability and reach, but whether navigation, target localization, and adequacy of sampling are superior to other techniques is less certain. Early data on diagnostic yields are encouraging, but multicenter prospective data are not yet available.

MEDICAL IMAGING

Imaging has revolutionized the practice of medicine. Technologies such as x-ray, CT, MRI, and positron emission tomography (PET) can provide noninvasive assessments of alveolar perfusion, the metabolic activity of a lung nodule, the bronchovascular source of hemoptysis, or the earliest disease-related changes in parenchymal structure. Given the breadth of advances in respiratory system imaging and increasingly specialized applications across diseases, the following section is organized by technology. The final part of this section is dedicated to deep learning and the role it is increasingly playing in medical image interpretation.

CHEST X-RAY

The field of medical imaging can be traced back to work done by Wilhelm Roentgen in the 1890s. Roentgen noted that after connecting a cathode ray tube to a power supply, material in his lab would fluoresce even if the emission of visible light from the tube was blocked. He quickly deduced the presence of additional invisible “x-rays” and subsequently observed that their passage through solid material was attenuated in proportion to the material’s density. Within weeks of its discovery, x-ray technology was being widely leveraged to guide surgical exploration and the extraction of foreign objects such as shrapnel from the battlefield. Chest x-ray (CXR) has since become the foundation of clinical practice for respiratory medicine and is a widely available technology even in resource-limited settings.

The most commonly used CXR images for respiratory medicine are the posteroanterior (PA) and lateral films in the outpatient setting and anteroposterior (AP) films for those studies obtained at the bedside. These are 2-dimensional representations of 3-dimensional structures and the differing views can be used to examine superimposed structures (for example, a parenchymal opacity in the retrocardiac space). The contours of the chest wall, the silhouette of the heart, great vessels, and mediastinum, as well as the appearance of the parenchyma and bronchovascular bundle are all used to detect and classify disease as well as monitor its progression or response to therapeutic intervention. An example of a normal PA and lateral CXR is provided in Fig. 286-4.

In this image of the normal lung, many of the smaller structures such as the lymphatics and distal airways are beyond the ability of conventional x-ray technology to resolve. Larger structures such as the pulmonary vasculature may also be indistinct because of body position and the redistribution of blood flow to more gravitationally dependent regions. Diseases involving these structures may enhance or obscure their appearance. An example of these diseases is congestive heart failure where the lymphatics become engorged (Kerley B lines), the nondependent vasculature more prominent (cephalization), and the outer boundaries of the bronchial walls blurred (bronchial cuffing). Each of these findings must be clinically contextualized and while a thickened interstitium may be due to hydrostatic pulmonary edema, it may also be indicative of interstitial lung disease or carcinomatosis. CXR can also be used to discriminate pulmonary and extra-pulmonary disease and because of that it is an excellent initial diagnostic for nonspecific symptoms. An elevated hemidiaphragm, fibrosis of the mediastinum, or hyperlucency of the lung parenchyma all reflect processes that cause dyspnea, but their treatment and prognosis differ markedly.

COMPUTED TOMOGRAPHY

CT was introduced to clinical care in the 1980s and quickly became one of the most heavily leveraged modalities for medical imaging. While CXR provides one or two views of the thorax from which an experienced clinician must disambiguate overlying structures, CT provides spatially resolved reconstructions of all structures in the thorax. The acquisition of a CT scan involves the same basic process as an x-ray with a patient placed between a source of photons and a detector, but the image reconstruction and advanced analytics that can be applied to those images differ markedly. The passage of photons through the body is impeded in proportion to tissue density. This absorption or attenuation of photon passage is measured in Hounsfield units (HU) and clinical CT scanners are regularly calibrated to a standard scale with water having an HU of 0 and air –1000 HU. The broad range of tissue densities (reflected as attenuation values) in the thorax and the limited human ability to visually discriminate between two structures of similar densities are addressed by modifying the image display. A window width and level (the range and center of the range of HU values to display) is selected to optimize viewing structures of interest. For example, lung windows are optimized for visual inspection of the low-density lung parenchyma and all of the surrounding higher-density structures appear white, whereas the mediastinal windows are optimized to view the higher-density structures and anything of lower tissue density such as the lung parenchyma appears black. This does not change the HU values of the voxels (3-dimensional pixels) in the image, just their presentation for visual inspection.

The visual interpretation of thoracic CT is based upon the appearance of the secondary pulmonary lobule. This structure is a fundamental subunit of the lung consisting of a central airway and pulmonary artery, parenchyma, and then surrounding interstitium with the lymphatics and pulmonary veins (Fig. 286-5).

Processes affecting the small airways such as respiratory bronchiolitis may appear as centrilobular nodules. Parenchymal diseases such as emphysema may begin by effacing the centroid of the lobule (CLE: centrilobular emphysema), the periphery of the lobule (PSE: paraseptal emphysema), or diffusely across the lobule (PLE: panlobular emphysema). Pathology of the lymphatics or interstitium (interstitial lung disease, ILD) results in beading and/or thickening of the interlobular septa. Examples of many of these processes are provided in Chaps. 292 and 293.

The diagnostic information provided by the appearance of the secondary pulmonary lobule is further augmented by the distribution of these patterns of injury across the lung. Whereas CLE tends to first appear in the upper lung zones, PLE has a predilection to be basilar predominant. Interstitial thickening in the apices is more likely to be nonspecific interstitial pneumonitis (NSIP) while a basal and dependent predominant distribution of that same process is more consistent with idiopathic pulmonary fibrosis (IPF).

Finally, morphology of the central airways and vessels can be used to diagnose disease and estimate its severity. Bronchiectatic dilation of the airways may be cylindrical and predominantly in the lower lobes as is seen in chronic obstructive pulmonary disease (COPD), cystic dilation in the upper lobes (cystic fibrosis), or there may be a focal nonspecific dilation of an airway due to prior infection. Pathologic dilation of the airways may also be due to disease of the surrounding parenchyma. Because of the mechanical interdependence of the bronchial tree and parenchyma, conditions that reduce lung compliance may result in traction bronchiectasis. This may be a local process or more diffuse depending on the distribution of the underlying parenchymal disease, and likely provides further insight into disease severity.

The caliber of the central pulmonary arterial (PA) trunk proximal to its first bifurcation is directly related to pulmonary arterial pressure. A measure of >3 cm is suggestive of the presence of elevated pulmonary vascular pressures and more recent studies have demonstrated that an increased ratio of the PA diameter to the diameter of the adjacent aorta (PA/A) provides a metric of disease severity and in the case of chronic respiratory diseases such as COPD is prognostic for both acute respiratory exacerbations and death. Assessment of the intraparenchymal pulmonary vasculature is typically augmented through the intravenous infusion or bolus of iodinated contrast. This bolus and subsequent image acquisition may be timed to visualize passage of contrast through the pulmonary arteries to enable detection of thromboembolic disease, which appears as dark filling voids in otherwise bright white vessels.

It must be noted that the acquisition of CXRs and thoracic CT scans involves exposing the patient to ionizing radiation. Several studies have estimated the excess numbers of cancer due to CT scanning and extensive efforts have been made by both CT manufacturers and clinicians to reduce the radiation dose to the lowest possible amount that does not jeopardize image quality and interpretability.

MAGNETIC RESONANCE IMAGING

MRI is based upon the behavior of protons in a magnetic field. A strong magnetic field is applied to align the protons and then a pulse of radiofrequency current is then applied to the subject. This perturbs the protons and the speed at which they subsequently realign differs based upon the properties of the tissues within the region of interest. While this technique provides exquisite imaging data for the chest wall or solid organs such as the brain or heart, the abundance of air in the lung creates an artifact that impairs direct assessment of the parenchyma. For this reason, MRI of the lung leverages intravenous contrast agents such as gadolinium and is increasingly exploring the use of inhaled agents such as hyperpolarized noble gas. These respective agents enable in vivo assessments of organ perfusion and detailed measures of the morphology of the distal airspaces. An example of noble gas–enhanced MRI is shown in Fig. 286-6. The inhaled agent is ³He and because it is proton rich, it can be used to examine lung ventilation visually and objectively. Regions of the lung that are poorly ventilated due to disease of the airways or distal airspaces have low concentrations of ³He and appear as dark regions in an otherwise bright blue organ.

While an MRI may have a longer acquisition time than CT, and the geometry of the equipment often leads to a sense of claustrophobia, it does not involve the administration of ionizing radiation. This makes it a modality of choice in the pediatric population or clinical situations where repeated assessments are required.

POSITRON EMISSION TOMOGRAPHY

PET generates an image based upon the aggregation of radiolabeled tracers. The most common agent used for these purposes is [¹⁸F]-fluoro-2-deoxyglucose (FDG). This radiolabeled glucose analogue is administered intravenously and is taken up by cells in direct proportion to their metabolic activity. In the clinical setting, it is most commonly used for the discrimination of benign and malignant lung nodules, as well as lung cancer staging. Given the relatively low resolution of PET, co-registration with CT is common and the aligned imaging modalities allow the reader to determine the structural source of heightened metabolic activity.

There is increasing interest in the use of PET imaging in the biomedical community. These applications are largely still confined to research but advances in areas such as in vivo assessments of vascular biology in acute and chronic disease have been impressive.

ARTIFICIAL INTELLIGENCE/DEEP LEARNING

The final aspect to thoracic imaging that must be discussed is the growing field of artificial intelligence and deep learning applied to image analysis. Classic machine learning approaches to medical image interpretation involve the development of advanced algorithms to detect structures of interest, segment their boundaries, and then extract metrics related to size, shape, texture, etc. The massive increase in processing capacity afforded by graphical processing units (GPUs), the increasing availability of large amounts of data, and the wide dissemination of open-source software libraries allowing developers to create powerful work environments has led to explosive growth in the utilization of deep learning for image analytics. Some of the first medical applications of deep learning were in the field of dermatology and, more recently, this advanced form of pattern recognition has been reported to excel at the discrimination of benign and malignant lung nodules in thoracic CT scan. The breadth of application of these tools continues to expand to include image navigation and feature detection, biomarker development, and direct prediction of clinical outcomes. An example of deep learning–enabled segmentation of the heart and pulmonary vasculature from noncontrast enhanced noncardiac gated CT scan is shown in Fig. 286-7.

TRANSTHORACIC NEEDLE ASPIRATION

Radiologically guided needle biopsy has served as a long-standing mechanism for evaluation of parenchymal lung lesions, both malignant and infectious. In the setting of published guidelines recommending low-dose screening CT scan for lung malignancy in high-risk patients and with evolving guidelines for monitoring and assessment of incidental lung lesions arising in this setting, radiologically guided sampling of lung lesions has become an increasingly important mechanism to address parenchymal lung abnormalities concerning for cancer. Moreover, as novel immune modulators and biologic agents are increasingly utilized for the management of systemic disease and transplantation, effective interventions are becoming progressively more important in assessing for potential pulmonary infections arising as complications of immune suppression. Transthoracic needle aspiration (TTNA) remains one important arm in the assessment of these pulmonary complications.

TTNA can be accomplished with a variety of complementary imaging mechanisms, including under fluoroscopic, CT, ultrasound, or MRI guidance. CT is currently the most common imaging modality used to assess parenchymal lung lesions, with sensitivity and specificity reported to be >90%. Sensitivity of CT-guided TTNA is increased in more peripheral lesions. Transthoracic ultrasound has the advantages of a low complication rate in the setting of fine needle aspiration (FNA) and portability, allowing for more logistical simplicity in the setting of lung lesion assessment. In a prospective study of ultrasound-guided percutaneous FNA compared with CT-guided FNA, diagnostic rates were comparable between the two groups, with shorter procedure time associated with ultrasound guidance, numerical suggestion of decreased complication rate using ultrasound guidance, and lower costs associated with ultrasound guidance. Use of elastography to better characterize lung lesions has also been proposed in the context of ultrasound, though additional diagnostic yield has not yet been proven. Color Doppler ultrasonographic imaging has been demonstrated to have a high sensitivity and specificity and a low complication rate in another study. Electromagnetic guidance, unlike CT imaging, can be used in combination with endobronchial ultrasound and or navigational bronchoscopy in the operative setting, theoretically allowing for a multimodal approach that could increase diagnostic yield and allow for a combined staging procedure. Electromagnetic TTNA alone has demonstrated an 83% diagnostic yield in a pilot study, with an increase to 87% when combined with navigational bronchoscopy. Conflicting data are available regarding the diagnostic superiority of TTNA compared with alternative biopsy modalities such as endobronchial ultrasound for diagnosis of lung lesions, and results may depend on center experience.

Transthoracic sampling can be obtained using FNA or core needle biopsy. In one retrospective study, FNA was found to have an inferior diagnostic rate, compared with core needle sampling, as well as lower specificity. In this study, a method involving two FNA passes was compared to core needle sampling with six cores obtained from a single pass. No significant differences in complication rates were noted. In another retrospective study, in which procedure was determined by operator preferences, core needle aspirate samples were more likely to provide sufficient material for molecular testing than FNA. A systematic review of these techniques concluded that insufficient evidence was available to support a difference between FNA and core needle biopsy in diagnostic efficiency, though core needle biopsy may be more specific in diagnosing benign lung lesions. Given the negative predictive value estimate of 70%, negative results from TTNA are less reliable than positive results and should not be considered definitive to eliminate the concern for malignancy. Further assessment is needed to directly compare imaging modalities for TTNA guidance and to compare TTNA with other diagnostic modalities to determine the optimal choice of procedure in particular settings. Choice of procedure should be considered in the context of the size and location of the lesion, the experience of the center and operator, and patient-specific factors.

In regards to the safety of TTNA, in a retrospective study from 2015, the presence of mild to moderate pulmonary hypertension in patients did not increase complication rates in the setting of TTNA. The complication rates noted in this report were substantial, however, with hemorrhage occurring in one-third to one-quarter of patients, and pneumothorax in 17–28%. The majority of pneumothoraces did not require chest tube placement. Other complications included hemoptysis and hemothorax, though these were uncommon. These complication rates are consistent with those reported in other studies. In a meta-analysis of complication rates of CT-guided TTNA, complication rates were higher with core needle aspirates than FNA (38.8% [95% CI 34.3–43.5%] vs 24% [95% CI 18.2–30.8%]). The majority of these complications were minor. Risk factors for complications with FNA included smaller nodule diameter, larger needle diameter, and increased traversed lung parenchyma. No clear risk factors were noted for complications after core needle biopsies in this publication. More generally, the risks of TTNA increase for more centrally located lesions and those residing in close proximity to intrathoracic vasculature.

Despite the outstanding questions regarding the optimal approach for TTNA, this modality has been shown to be effective in cancer diagnosis in the thorax. Adenocarcinoma has become the most prevalent parenchymal lung malignancy in reported studies, and also the most common malignant diagnosis found on TTNA of the lung. TTNA can also be effective in diagnosing less common tumors of the lung, both malignant and benign, including squamous and small cell carcinomas, lymphomas, and others, as well as in assessing tumors of the mediastinum. The diagnostic utility of TTNA is consistent across solid, subsolid, and partially calcified lung nodules. Immunocytochemistry markers can be utilized in TTNA samples to assist with diagnosis, prognosis, and prediction of response to therapy, and samples should be preserved whenever possible to allow for these studies, if needed. RNA extraction has also proven feasible in the setting of a single FNA sample, which could be instrumental in gene expression profiling, though this has thus far only been successfully accomplished in a research context.

The utility of TTNA in diagnosing pulmonary infections is variable in published literature. Some publications have reported that TTNA establishes a diagnosis of infection in 60–70% of cases, with a particularly high yield in the setting of Aspergillus infections. TTNA has also been shown to be particularly effective in the diagnosis of pulmonary tuberculosis, though a wide variety of infections have been diagnosed using this method. The presence of necrosis in lung lesions makes establishing an infectious diagnosis more likely using TTNA. Numerous staining techniques are available to assist with infectious diagnoses, and immunohistochemistry can also aid in the diagnosis of infection. Cytology should be correlated with histopathology and culture results, when available. Metagenomics using next-generation sequencing for detection of infection is evolving but requires further study. TTNA has also been useful in identifying granulomatous inflammation, which can provide supportive evidence of a granulomatous parenchymal lung disease in the appropriate clinical setting.

In summary, TTNA is an important element of diagnostic algorithms in the setting of lung nodules and masses, particularly when concern for malignancy is not high enough to warrant immediate excision, when the patient is not a surgical candidate, or the lesion or disease is not amenable to surgical resection. Further study is needed, however, to better understand the role of TTNA and other diagnostic modalities in the evaluation of parenchymal lung lesions.

MISCELLANEOUS TESTING

SPUTUM TESTING

Sputum microscopy and culture are commonly utilized to diagnose respiratory tract infections and identify the causative organisms. In patients with productive cough the sampling is simple and noninvasive, however, subject to patient technique and the potential for oropharyngeal and/or upper respiratory tract contamination. In those who are not expectorating, sputum induction can be considered using provocative nebulization with saline. Numerous studies have attempted to define criteria for reliability and reproducibility of sputum samples. The majority include quantification of number of epithelial cells and white blood cells per low power field, and many assess the ratio of the two for adequacy of sampling. None has been confirmed as superior in establishing the reliability of sampling to reflect lower respiratory tract growth. The quality of the sputum sample directly impacts the diagnostic reliability in the setting of bacterial pneumonia. Growth of Mycobaterium tuberculosis, Legionella, or pneumocystis should raise concern for infection, even in the setting of a poor sample. Endotracheal aspirates have not been demonstrated to be clearly superior to expectorated sputum in terms of diagnostic reliability, but such sampling may be required if spontaneous coughing is nonproductive and induced sputum is not feasible or successful.

As in the context of infection, sputum cytologic analysis has been utilized to assist in the diagnosis of malignancy, mainly because it can be obtained noninvasively. While sputum cytology demonstrating malignant cells is highly specific for a diagnosis of lung malignancy, its sensitivity has been reported at <40%. A systematic review of screening methods demonstrated no added benefit from sputum cytology when combined with CXR to screen for lung cancer. Advanced molecular techniques such as polymerase chain reaction, DNA methylation markers, micro-RNA assessment, and tumor-related protein analysis have been proposed in sputum assessment for diagnostic purposes and risk stratification. At present, however, sputum cytology is recommended only when more invasive techniques cannot be pursued, such as in patients with prohibitive comorbidities or in resource-limited settings.

EXHALED BREATH CONDENSATE

Exhaled breath condensate includes gaseous, liquid, and water-soluble components, with numerous biomarker types and collection system varieties developed over time. Validation standards for many components are still being determined. Exhaled nitric oxide is the most highly validated of the biomarkers identified in exhaled breath condensate. The fraction of exhaled nitric oxide (FeNO) has been demonstrated in higher concentrations in exhaled breath condensate of patients with asthma than in healthy individuals, and has been shown in some studies to correlate with the presence of eosinophils in the sputum and blood and with response to inhaled corticosteroids, though data are conflicting. For example, in a systematic review and meta-analysis, FeNO elevation increased the odds of having asthma in both children above the age of 5 years and adults. In another systematic review of FeNO utilization in the management of adults with asthma, the assessment was helpful in the management of severe exacerbations but had no significant impact on overall exacerbations or inhaled corticosteroid use. Moreover, evidence suggests that tailoring of asthma therapy based on sputum eosinophil levels was effective in decreasing asthma exacerbations, but tailoring of therapy based on FeNO was not beneficial in improving outcomes, and insufficient evidence was observed to advocate the use of either sputum analysis or FeNO in clinical practice. FeNO has also been shown to be influenced by ethnicity, and appropriate reference standards for different ethnic groups have yet to be established. While FeNO has been proposed as a potential clinical guide to management, its use has not been incorporated into all guideline recommendations, and it has not been formally approved for clinical use.

SWEAT TESTING

Assessment of chloride concentration in sweat using pilocarpine iontopheresis, or sweat testing, remains a key element in the diagnostic framework of cystic fibrosis (CF). This method utilizes pilocarpine to stimulate sweat production. As patients with CF suffer from alterations to the sodium chloride ion channel, measurement of electrolytes in their secretions such as sweat reveals elevated chloride concentrations, amongst other abnormalities. This testing has been considered the gold standard in the diagnosis of CF due to its functional nature, its relative noninvasiveness, the establishment of validated standards for its performance, and its ability to discriminate between healthy individuals and those with CF at a chloride concentration of ≥60 mmol/L. The likelihood of a diagnosis of CF at a concentration of <40 mmol/L has been observed to be low, and an indeterminate range was defined as 40–59 mmol/L, which could be consistent with the disease if genetic and clinical manifestations were supportive.

While functional testing such as sweat chloride testing remains an essential component of diagnostic algorithms in CF, the evolution of genetic analysis has led to identification of an extensive array of genetic mutations associated with varied phenotypic impacts in this disease. In this context, the indeterminate range of chloride concentrations of 40–59 mmol/L on sweat test analysis was found to inadequately identify milder or more heterogenous forms of the disease associated with newly identified genetic mutations. As a result, the Cystic Fibrosis Foundation provided updated guidance for the interpretation of sweat test results, with a decreased lower threshold to define an intermediate range of chloride concentration (changed from 40–50 mmol/L to 30–50 mmol/L), which could be consistent with the diagnosis of CF in the appropriate genetic and clinical context. In a subsequent analysis, utilization of the new guidance was found to enhance the probability of identifying patients with CF without increasing the false-positive diagnosis rate in the population. Sweat testing is a critical component of the CF diagnostic algorithm but should be interpreted in the context of clinical manifestations of disease and correlated with genetic testing in those suspected of the diagnosis.

ALLERGY TESTING

Allergy testing is often considered in the assessment of environmental exposures, including seasonal allergens, food allergens, and drug allergens. In the case of drug allergens in particular, drug reactions are often reported based on remote history and are often unconfirmed. The hesitancy to re-expose patients with an unconfirmed drug allergy can lead to limited options for treatment, to delay in treatment, and to utilization of treatments with more extended spectrum, potentially influencing the resistance patterns of these agents. Drug reactions can be mediated by IgE (immediate type reactions, type I), IgG or IgM (type II), immune complex reactions (type III), and delayed-type hypersensitivity reactions mediated by cellular immune mechanisms (type IV).

Skin testing, including patch testing and/or delayed intradermal testing, is available to test exposure to particular allergens and determine reactivity. These tests have been shown to aid in clinical phenotyping of type I reactions and potentially in type IV reactions, though their role in type IV assessment remains more controversial. In the context of suspected type I reactions, patch testing is more cost effective and may be as effective as intradermal testing in identifying potential causative agents. The negative predictive value of intradermal skin testing in assessing for IgE-mediated drug allergies is high; however, the high sensitivity of this testing limits its specificity, and results must be interpreted in the context of the pretest probability and the clinical experience of the patient. Skin tests have also been demonstrated to assist in identifying the causative agent in type IV reactions and to assess cross-reactivity between structurally related drugs. Intradermal testing may be more sensitive than patch testing to assess for type IV drug reactions. Though some debate continues regarding a mandatory role for skin testing in the assessment of potential drug allergies, drug provocation testing or rechallenge is generally regarded as safe in low-risk individuals with history of urticaria or immediate rash, whereas skin testing has been proposed as a preliminary assessment in higher-risk individuals with a history of two or more reactions, angioedema, or anaphylaxis, prior to consideration of drug provocation testing.

FURTHER READING