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CHAPTER 15 Evaluating Lung Structure and Function
Alveolar
cells
180.e1
Normal
O
2
CO
2
Vessel
Emphysema
E-Fig. 15.3 A photomicrograph of normal and emphysematous lungs. Notice the lack of alveolar septa in the
emphysematous lung.
CHAPTER 15 Evaluating Lung Structure and Function
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181
TABLE 15.2 Normal Values for Arterial
Blood Gases
Partial pressure of oxygen (Pao2): 104 − (0.27 × age)
Partial pressure of carbon dioxide (Paco2): 36-44
pH: 7.35-7.45
Alveolar-arterial O2 difference = 2.5 + (0.21 × age)
6-Minute Walk Distance
Often, alterations in oxygenation are not detected at rest but are
unveiled during exertion. The 6-minute walk test is a standardized test
in which the patient walks for 6 minutes while the oxygen hemoglobin saturation is measured. A decrease in saturation is abnormal and
suggests impaired gas exchange capabilities, and a reduction in distance walked is a means of detecting deterioration of overall function
due to lung disease. However, the 6-minute walk distance (6MWD)
is primarily validated for following exercise capacity over time and in
response to interventions. There is a “learning effect” that increases
distance walked after the first attempt, and the minimal clinically
important distance for this test is established as 30 meters. The 6MWD
correlates well with peak oxygen consumption (VO2 max) measured
with maximal exercise testing.
In summary, pulmonary function tests, in conjunction with the
history and physical examination, can be used to diagnose pulmonary
disorders and assess severity and response to therapy, as illustrated in
the flow diagram in E-Fig. 15.4.
EVALUATION OF LUNG DISEASE
Analysis of Exhaled Breath
Endogenously produced monoxides (nitric oxide and carbon monoxide) and volatile organic compounds (VOCs), collectively called the
“volatolome,” can be detected in the exhaled breath and may serve
as biomarkers of pulmonary inflammation or cancer. Exhaled nitric
oxide is elevated in asthma, and the US Food and Drug Administration
has approved the test for exhaled nitric oxide for the diagnosis and
evaluation of asthma exacerbations. The VOCs can be detected by gas
chromatography or mass spectroscopy but more recently electronic
“noses” have been developed that use changes in electrical resistance of
polymers that bind VOCs to detect unique patterns of exhaled VOCs.
These provide a “fingerprint” that may identify lung cancer, various
pneumoconioses, obstructive sleep apnea, active pulmonary tuberculosis, and pulmonary hypertension. Cytokines and other similar
compounds in the condensate phase of exhaled breath are being investigated for possible applications in inflammatory lung diseases (e.g.,
cystic fibrosis, bronchiectasis). Other nonpulmonary diseases such as
malabsorption syndromes and Helicobacter pylori infection are also
detected by analysis of exhaled breath.
Chest Radiography
Generally, the evaluation of a patient with lung disease begins with
routine chest radiography and then proceeds to more specialized
techniques such as computed tomography (CT) or magnetic resonance imaging (MRI). Ideally, the chest radiograph consists of two
different films, a posteroanterior (PA) radiograph and a lateral radiograph (E-Fig. 15.5). Many pathologic processes can be identified on a
PA chest radiograph, and the lateral view adds valuable information
about areas that are not well seen on the PA projection. In particular, the retrocardiac region, the posterior bases of the lung, and the
bony structure of the thorax (e.g., the vertebral column) are better visualized on the lateral radiograph. The PA chest radiograph is
obtained with the patient standing with his or her back to the x-ray
beam and the anterior chest wall placed against the film cassette. The
chest radiograph should be obtained while the patient takes the deepest breath possible. If the patient is too weak to stand or too sick to
travel to the radiology department, the chest radiograph is performed
at bedside (portable chest radiograph). The cassette is placed behind
the patient’s back while the patient is semi-supine in bed, and the
x-ray beam travels from anterior to posterior (AP film). The quality
of a portable film is not that of a standard PA film, but it still provides
valuable information.
The examination of a chest radiograph should be systematic so
that subtle abnormalities are not missed. It should include evaluation
of the lungs and pulmonary vasculature, the bony thorax, the heart
and great vessels, the diaphragm and pleura, the mediastinum, the
soft tissues, and the subdiaphragmatic areas. Abnormalities that are
visible on a chest radiograph include pulmonary infiltrates, nodules,
interstitial markings, vascular abnormalities, masses, pleural effusions
and thickening, cavitary lesions, cardiac enlargement, abnormal airway structure, and vertebral or rib fractures. In addition to the PA and
lateral chest radiographs, the lateral decubitus projection is often used
to identify the presence or absence of pleural effusion. The decubitus
view is particularly useful in determining whether blunting of the costal phrenic sulcus is caused by freely flowing pleural fluid or related to
pleural thickening. Chest radiography, in concert with a good history
and physical examination, allows the clinician to diagnose chest disease in many circumstances.
Fluoroscopy
Fluoroscopic examination of the chest is useful for evaluating
motion of the diaphragm. This technique is particularly helpful
in diagnosing unilateral diaphragm paralysis. A paralyzed hemidiaphragm moves paradoxically when the patient is instructed to
inhale or to forcefully sniff. However, fluoroscopy is limited when
evaluating for bilateral diaphragm paralysis. Apparently normal
descent of the diaphragm during inspiration, caused by compensatory respiratory strategies employed by the patient with bilateral
diaphragm paralysis, leads to false-negative results. False-positive
results are caused by paradoxical hemidiaphragm motion, which
can be seen in as many as 6% of normal subjects during the sniff
maneuver.
Ultrasonography
Point-of-care ultrasonography (POCUS) has improved clinical care
by providing more focused and visual examinations of vital organs to
aid in prompt diagnosis and management of diseases. In ultrasonography, sound waves in the frequency range of 3 to 10 MHz are reflected
off internal tissues to produce images of viscera such as the liver,
kidney, and heart. The air-filled lung cannot be imaged directly, but
over the last decade, an understanding of various artifacts generated
by ultrasound beams traversing normal and abnormal lung have led
to increased application of ultrasound for imaging of the lung, particularly in the intensive care unit. Protocols are available to help with
detecting lung consolidation, pulmonary edema, and volume responsiveness. Additionally, ultrasonography can rapidly and reliably detect
a pneumothorax, pleural effusion, consolidation, and pulmonary
Dyspnea
History and
physical examination
CHAPTER 15 Evaluating Lung Structure and Function
Tests
Test Results
Diagnosis
181.e1
Normal
(? Asthma)
Broncho-
provocation
test
Hyperreactive
airways
Obstructive pattern
Asthma
COPD
Other
LCO
D
Low
Pulmonary
function
tests
(reduced FEV
and FEV1/FVC)
Change in FEV
after bronchodilator
Normal
12% improvement
Restrictive
(reduced TLC)
1
pattern
1
Chest wall defects
Neuromuscular disorders
Interstitial lung disease
Abnormal
Neuromuscular
chest wall defect
MVV
NIF test
Normal
Normal
DLCO
Abnormal
Cardiac
evaluation
Emphysema ILD
Asthma
Chronic bronchitis
Congestive heart
failure
E-Fig. 15.4 The flow diagram shows how pulmonary function tests can be used to evaluate patients with
obstructive and restrictive disorders. COPD, Chronic obstructive pulmonary disease; Dlco, diffusing capacity
for carbon monoxide; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; ILD, interstitial
lung disease; MVV, maximum voluntary ventilation; NIF, negative inspiratory force; TLC, total lung capacity.
Normal
E-Fig. 15.5 Normal posteroanterior (left) and lateral (right) chest radiographs.
182 SECTION III Pulmonary and Critical Care Medicine
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edema with sensitivity and specificity similar to those of a chest radiograph (Fig. 15.24).
In addition to its diagnostic capabilities, ultrasound is routinely
used in real time to direct invasive procedures, such as thoracentesis, pericardiocentesis, and placement of a pleural, central venous, or
arterial catheter. Other applications of pulmonary ultrasound include
assessment of volume status by imaging inferior vena cava collapsibility with respiration and assessment of right ventricular function.
Two-dimensional B-mode ultrasound imaging of the diaphragm can
be used to visualize diaphragm function during inspiration. Failure of
the diaphragm to thicken by a minimum of 35% during inspiration
when visualized from the infraaxillary view is indicative of diaphragm
weakness.
Ultrasonography is noninvasive, rapidly and easily applied, relatively low-cost, readily portable to the bedside, and because it does not
use radiation, safe for repeated use on a patient.
Computed Tomography
CT has many applications in pulmonary medicine and provides more
detailed information about lung structure than chest radiography.
With the use of this technique, cross sections of the entire thorax can
be obtained, usually at 2- to 5-mm intervals. CT scanning allows visualization of airways up to the seventh generation and delineation of
parenchymal anatomy, texture, and density. Image contrast can be
adjusted to optimize visualization of the lung parenchyma, pleura, and
Fig. 15.24 Ultrasound image of the lung depicts the diaphragm, a pleu-
ral effusion, and an infiltrate.
mediastinal structures. The use of intravenous contrast material as part
of the examination permits separation of vascular from nonvascular
mediastinal structures. CT scans provide tremendous anatomic resolution when compared with chest radiography, but they expose the
subject to about 70 times the radiation of a routine chest radiograph.
CT of the chest helps characterize pulmonary nodules and masses,
distinguish between pleural thickening and pleural fluid, estimate the
size of the heart and the presence of pericardial fluid, identify patterns
of involvement of interstitial lung disease, detect cavities, and identify
intracavitary processes such as mycetoma. It is also used to quantify
the extent and distribution of emphysema, detect and measure mediastinal adenopathy for evaluating inflammatory diseases that involve
mediastinal lymph nodes (e.g., sarcoidosis) and staging of lung cancer,
and identify vascular invasion by neoplasm (Fig. 15.25). Newer generations of CT scanners are able to use multiple x-ray beams to create
between 4 and 256 images simultaneously at a much faster rate (<10
seconds) than with the older models, which used only a single x-ray
beam and detector. CT scans using much lower radiation doses are
routinely advocated on a yearly basis for the early detection of lung
cancer in older, high-risk smokers.
CT angiography allows for construction of three-dimensional
images of the pulmonary vascular system. This imaging technique has
emerged as the procedure of choice for identifying pulmonary embolism, supplanting pulmonary ventilation-perfusion scintigraphic lung
scanning. The technique is used to identify pulmonary vascular abnormalities such as aortic dissection, pulmonary venous malformations,
and aortic aneurysms. Additionally, three-dimensional construction
of the airway and pulmonary parenchyma using CT images and specialized software has provided a means to electromagnetically guide a
biopsy catheter through a bronchoscope (electromagnetic navigation
bronchoscopy) to a distal pulmonary nodule or mass for biopsy. It
could also be used to place a fiducial marker at the exact location of
a lung cancer to accurately focus surgical or radiotherapy treatment.
Dynamic contrast-enhanced CT with single- or multi-detector
scanner has been investigated as a modality to differentiate between
a malignant and benign pulmonary nodule. First, baseline images are
obtained using CT without contract enhancement. Subsequently, contrast is given over time while series of CT images are acquired. The
difference time and contrast enhancement allow for evaluation of vascularity and blood flow patterns. Studies have confirmed high accuracy
for differentiation.
High-resolution CT is a technique that generates thin (1-mm)
anatomic slices to provide a high-contrast image of the pulmonary
AB
Fig. 15.25 Chest radiograph (A) and chest computed tomographic (CT) scan (B) of a patient with severe
bronchiectasis. The abnormally dilated airways are better appreciated on the CT scan.
CHAPTER 15 Evaluating Lung Structure and Function
parenchyma. With high-resolution CT, a special reconstruction algorithm sharpens the soft tissue interfaces to provide superior visualization of the pulmonary parenchyma. This technique is used primarily
to identify interstitial lung disease and bronchiectasis. It is extremely
useful for identifying interstitial lung disease that may not be apparent
on a plain chest radiograph, and it has supplanted bronchography in
the diagnosis of bronchiectasis.
Magnetic Resonance Imaging
MRI is a tomographic technique that uses radio waves modified by
a strong magnetic field to produce an image resulting from the resonation of protons in tissue water. The chief advantage of MRI is that
it does not entail the use of ionizing radiation. The ability of MRI
to image pulmonary parenchyma is limited because of the low proton density in air-filled regions of the lung, which therefore cannot
generate MRI images, artifacts arising from multiple air-tissue interfaces, and respiratory motion artifacts. However, vascular structures
and pulmonary perfusion are well imaged by MRI, especially with
the use of intravenous contrast agents such as gadolinium chelates.
Therefore, MRI is very useful in the study of aortic dissection and
may have a role in the evaluation of pulmonary emboli and chronic
thromboembolic pulmonary hypertension. Three-directional velocity-encoded MRI allows three-dimensional, time-resolved cine reconstruction of blood flow patterns and pressures and is used in cardiac
imaging. It may also have a role in the measurement of pulmonary
blood flow. Infiltrative pulmonary diseases and pulmonary edema
increase proton density in the lung, allowing better definition by
MRI of honeycombing in pulmonary fibrosis and pulmonary edema
in acute respiratory distress syndrome (ARDS). The use of inhaled
hyperpolarized inert gases such as helium-3 or xenon-129 offers the
ability to quantify peripheral airspace size, measure gas flow in lobar
and segmental bronchi, and detect regional differences in ventilation.
Ongoing studies are being completed to establish its utility. It has
promising applications in the evaluation of emphysema and asthma
and after lung transplantation, including assessment of bronchodilator responsiveness. In particular, MRI is very useful in delineating extension of malignant pleural mesothelioma to adjacent chest
wall tissue or diaphragm, where it is much superior to CT imaging
because of superior contrast resolution.
Pulmonary Angiography
Pulmonary angiography entails placement of a catheter in the pulmonary artery, followed by rapid injection of a contrast agent. In the past,
this was “gold standard” for diagnosis of pulmonary thromboembolic
disease. Pulmonary angiography still can be useful for detection of
congenital abnormalities of the pulmonary vascular tree, but CT and
MRI have largely supplanted it.
Pulmonary Ventilation-Perfusion Scanning
Ventilation-perfusion (V
ticals such as technetium-99m as a noninvasive means to evaluate
regional blood flow and ventilation. Therefore, it has been used in the
past as an alternative to pulmonary angiography to detect pulmonary
embolism. With the advent of CT angiography and its improvements
over the years, V
uation of suspected pulmonary embolism. Additionally, alteration of
regional blood flow (pulmonary vasoconstriction and shunt) due to
lung diseases such as pneumonia or interstitial lung disease limits its
diagnostic accuracy. The PIOPED study in 1990 investigated the diagnostic accuracy of a V
lism. The study found that a V
probability is high but that it has poor diagnostic accuracy. Despite
.
.
/Q.) scintigraphy utilizes radiopharmaceu-
/Q. imaging is no longer favored for the initial eval-
.
/Q. scan for the diagnosis of pulmonary embo-
.
/Q. scan is useful when the clinical pretest
183
.
its limitations, V
These scenarios include patients who have abnormal renal function,
patients who are allergic to CT contrast, and patients with suspected
chronic thromboembolic pulmonary hypertension (higher sensitivity
compared to CT angiography). Quantitative lung perfusion scanning
is also very useful preoperatively to assess the predicted postoperative
lung function remaining after planned lobectomy or pneumonectomy. Therefore, it is used by thoracic surgeons to evaluate a patient’s
suitability for undergoing lobectomy or pneumonectomy for curative
resection of lung cancer.
/Q. scan still has utility in certain clinical scenarios.
Positron Emission Tomography
Positron emission tomography (PET) detects metabolically active
pulmonary nodules greater than 0.8 cm in diameter. It is helpful in
assessing whether a nodule is benign or malignant. However, it does
not distinguish between inflammation and malignancy. Therefore,
assessment of multiple pulmonary nodules by PET is limited because
of false-positive findings due to active granulomatous disease, such as
previous exposure to tuberculosis, sarcoidosis, or fungal infestation; or
to active infection, such as bacterial or viral pneumonia, bronchiolitis,
or aspiration.
Dual-modality integrated PET-CT combines morphologic and
functional imaging. The combination of PET and CT is helpful for
localizing solitary metastatic lymph nodes in the hila and extrapulmonary locations, allowing better staging of lung cancer. In addition,
PET-CT is helpful in planning radiation therapy for patients who have
lung cancer associated with atelectasis.
Bronchoscopy
Fiberoptic bronchoscopy is used for diagnostic or therapeutic indications. It is most commonly performed to directly visualize the nasopharynx, larynx, vocal cords, and proximal tracheobronchial tree
for diagnostic purposes. The procedure is performed by sedating the
patient and providing local anesthesia with inhaled and instilled lidocaine. The bronchial mucosa is assessed for endobronchial masses,
mucosal integrity, extrinsic compression, dynamic compression, and
hemorrhage. The bronchoscope is equipped with a channel for passing
a variety of instruments including biopsy forceps for sampling endobronchial lesions or lung tissue (transbronchial biopsy), and fine 19to 22-gauge needles for transbronchial aspiration biopsy from lymph
nodes or lung masses. Saline also can be instilled through the channel
for bronchial washings or bronchoalveolar lavage. Bronchial washings
and bronchoalveolar lavage can be analyzed for cytology, culture, and
special stains. A bronchial brush is used to scrape the bronchial mucosa
and harvest cells for cytology. Bronchoscopes can also be adapted with
a terminal ultrasound probe to provide ultrasound images of the airways and neighboring tissues. This technique, called endobronchial
ultrasound (EBUS) uses high acoustic frequencies, in the range of 20
MHz, to provide high-resolution images of proximal tissue and provides accurate positional guidance for needle aspiration of mediastinal
lymph nodes. It is now routinely used to detect lung cancer metastasis
to mediastinal lymph nodes and for the diagnosis of granulomatous
disorders of the lymph nodes. A different radial ultrasound probe
inserted through the working channel of a bronchoscope can facilitate
confirmation of the position of a transbronchial biopsy forceps near a
lung mass during transbronchial biopsy of a lesion in the periphery of
the lung parenchyma. A newer technique called transbronchial lung
cryobiopsy (TBLC) uses a probe that traverses the working channel of
a bronchoscope into the periphery of the lung near the chest wall. The
probe is rapidly cooled to freeze the adjacent lung tissue, which adheres
to the probe and is fractured off, resulting in biopsy specimens that
are larger and less susceptible to the crush artifact noted on routine
184 SECTION III Pulmonary and Critical Care Medicine
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forceps biopsies. This technique, though often complicated by serious
hemorrhage, is in use for the diagnosis of interstitial lung disease with
the hope that it will obviate the need for surgical biopsy.
Common therapeutic indications for bronchoscopy include retrieval of
foreign bodies, suctioning of secretions, reexpansion of atelectatic lung by
removing obstruction, detection and localization of hemoptysis, and assistance with difficult endotracheal intubations. In special centers, bronchoscopy is used to perform yttrium aluminum garnet (YAG) laser therapy,
argon plasma coagulation therapy, and cryotherapy for endobronchial
lesions. It is also used to guide placement of catheters for brachytherapy
in lung cancer or guide placement of stents. Lasers produce a beam of
light that can induce tissue vaporization, coagulation, and necrosis. Argon
plasma coagulation therapy uses heat from ionized argon gas to debulk
the tumor while simultaneously coagulating to stop bleeding. Cryotherapy
probes induce tissue necrosis through hypothermic cellular crystallization
and microthrombosis. Cryotherapy and electrocautery have been used
to treat and relieve airway obstruction caused by benign tracheal bronchial tumors, polyps, and granulation tissue. The goal of endobronchial
brachytherapy is to relieve airway obstruction from central tumors. This
is typically used as an adjunct to conventional external-beam irradiation.
Tracheobronchial stenting can be performed to manage airway compression associated with malignant tumors, tracheoesophageal fistulas, or
tracheobronchomalacia. Bronchoscopy is generally a safe procedure with
major complications, including significant bleeding, pneumothorax, and
respiratory failure, occurring in 0.1% to 1.7% of patients.
PROSPECTUS FOR THE FUTURE
Continued refinement and evolution of techniques and methods currently used to assess pulmonary structure and function will enhance
the ability to diagnose and treat individuals with lung disease.
Although pulmonary function testing has been performed for decades,
advances in equipment design and better standardization of methods will improve accuracy and reproducibility. Further development
of noninvasive techniques used to measure changes in lung volume
from body surface displacements may allow for assessment of pulmonary function in settings outside the pulmonary function laboratory.
Analysis of exhaled gas for biomarkers has tremendous potential for
early diagnosis of many lung diseases, especially cancer.
Great strides in assessing lung structure will evolve from advances
in CT, PET, and MRI technology. CT volume-rendering techniques
will provide images of the central airways, enabling “virtual bronchoscopy.” This technique will be useful to guide biopsy site selection
in conventional bronchoscopy and to allow visualization of airways
distal to an endobronchial obstruction. Volumetric measurements
of pulmonary nodules using CT segmentation techniques will allow
more accurate calculation of nodule volume and better assessment
of tumor doubling times. This, in concert with PET-CT, may provide more accurate means of determining the malignant potential of
a solitary pulmonary nodule. Also, dynamic contrast-enhanced CT
may help with differentiating between malignant and benign pulmonary nodules that would further improve the lung cancer screening
process.
MRI may evolve into the preferred method for evaluating pulmonary emboli, mediastinal disease, and regional ventilation-perfusion matching. Velocity-encoded MRI is a promising modality for
assessment of pulmonary vascular blood flow and pressures and may
prove to be more accurate than current noninvasive methods. Lymph
node–specific magnetic resonance contrast agents and the development of PET molecular tracers targeting tumor proteins and receptors
may better differentiate enlarged lymph nodes caused by hyperplasia
from those due to neoplasia. Finally, new insights into the function
of the respiratory control centers in the cortex and brain stem may be
attained from the use of functional MRI studies of the brain.
SUGGESTED READINGS
McCool FD, Hoppin FG Jr: Respiratory mechanics. In Baum GL, editor:
Textbook of pulmonary diseases, Philadelphia, 1998, Lippincott-Raven, pp
117-130.
McCool FD, Tzelepis GE: Current clinical aspects of diaphragm dysfunction,
N Engl J Med 366:932-942, 2012.
Miller WT: Radiographic evaluation of the chest. In Fishman AP, editor:
Fishman’s pulmonary diseases and disorders, New York, 2008, McGraw-
Hill, pp 455-510.
Pellegrino R, Viegi G, Brusasco V, et al: Interpretative strategies for lung
function tests, Eur Respir J 26:948-968, 2005.
Wagner PD: Ventilation, pulmonary blood flow, and ventilation-perfusion
relationships. In Fishman AP, editor: Fishman’s pulmonary diseases and
disorders, New York, 2008, McGraw-Hill, pp 173-189.
Weibel ER: It takes more than cells to make a good lung, Am J Respir Crit
Care Med 187:342-346, 2013.
West JB: Respiratory physiology: the essentials, ed 5, Baltimore, 1995, Williams
& Wilkins.
West JB, Wagner PD: Pulmonary gas exchange, Am J Respir Crit Care Med
157:S82-S87, 1988.
16
Obstructive Lung Diseases
Zoe G.S. Vazquez, Matthew D. Jankowich, Debasree Banerjee
INTRODUCTION
The obstructive lung diseases are a group of pulmonary disorders that
result in dyspnea characterized by an obstructive pattern of expiratory airflow limitation on spirometry. These disorders include chronic
obstructive pulmonary disease (COPD), asthma, cystic fibrosis (CF),
bronchiectasis, and bronchiolar disorders. In some cases, these disorders overlap clinically (Fig. 16.1), sharing several features aside from
the presence of expiratory airflow limitation. These features may
include symptoms of wheezing and sputum production, chronic airway-centered inflammation, presence of airway structural changes
resulting in remodeling of the airways, and episodic periods of temporarily worsened clinical status, known as exacerbations. However,
the causes, locations, and patterns of airway inflammatory changes and
remodeling, as well as the treatments, prognoses, and natural histories, are often significantly different, making clinical distinction among
these disorders important.
COPD is characterized by abnormal airway inflammation and
lung structure in response to an inhaled irritant (typically cigarette
smoke), resulting in irreversible or incompletely reversible airflow
limitation that is typically progressive over time. Asthma is distinguished from COPD by characteristic smooth muscle hyperreactivity
and reversible airflow limitation, by its variable clinical course, and
by its frequent association with atopy. These disorders are epidemic
Bronchiolar
Bronchiectasis
CF
Asthma
Fig. 16.1 Classification of obstructive lung diseases. Although most
patients with chronic obstructive pulmonary disease (COPD) have small
airways disease, the bronchiolar disorders do not overlap with COPD.
CF, Cystic fibrosis.
disorders
(excluding
COPD)
COPD
in the general population worldwide and account for a significant
proportion of the morbidity and mortality associated with the
obstructive lung diseases. Bronchiectasis is a permanent abnormal
dilation of the bronchi that results in chronic cough, purulent sputum production, and hemoptysis. Bronchiectasis is caused by diverse
conditions including CF, a genetic disorder resulting from mutations
in the CFTR gene. The bronchiolar disorders, also called small airways
disorders, result from inflammation and/or fibrosis of the small airways of the lung that leads to dyspnea. They may be difficult to diagnose because loss or obstruction of a majority of the small airways
must occur before the appearance of expiratory airflow limitation on
spirometry.
The basis for expiratory airflow obstruction varies among these
disorders. The flow of air through the bronchial tree is directly proportional to the driving pressure and inversely proportional to the
resistance. In obstructive lung disease, alterations in one or both of
these processes may be present. Loss of lung elastic tissue, frequently
present in COPD, results in decreased lung elastic recoil on expiration and therefore decreased driving pressure for expiratory airflow.
By contrast, airflow limitation in asthma is primarily caused by smooth
muscle contraction resulting in bronchoconstriction that increases airway resistance. Increases in airway resistance are also present in COPD
and are related to small airway inflammation and fibrosis as well as
small airway collapse due to decreased “tethering” of the airways in the
setting of loss of surrounding lung elastic tissue. Mucus obstruction
of airway lumens contributes to increased airway resistance in all the
obstructive lung diseases.
Obstruction to airflow causes characteristic changes in lung volumes. The residual volume (RV) and functional residual capacity
(FRC) are increased, whereas the total lung capacity (TLC) remains
normal or is increased. Vital capacity, and particularly inspiratory
capacity, is eventually reduced by the increase in RV. Several factors may contribute to the increase in FRC and RV in obstructive
lung disease. Decreased lung elastic recoil in COPD increases the
FRC because of reduced opposition to the outward force exerted
by the chest wall. Loss of airway tone and decreased tethering by
the surrounding lung in COPD, as well as bronchoconstriction and
mucus plugging in acute asthma, allow airways to collapse at higher
lung volumes and trap excessive air. Finally, under demands for
increased minute ventilation (e.g., during exercise), the increased
resistance to airflow may not allow the lungs to empty completely
in the time available for expiration; this leads to so-called dynamic
hyperinflation of the lungs as the volume of trapped air progressively increases while the inspiratory capacity is progressively limited. This phenomenon contributes to symptoms of chest tightness
and dyspnea during exercise and results in exercise limitation, especially in COPD.
185
186 SECTION III Pulmonary and Critical Care Medicine
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TABLE 16.1 Features of Obstructive Lung Disease
Disorder Clinical Features Laboratory Findings
Chronic obstructive pulmonary disease Chronic progressive dyspnea
Cough, sputum production
Periodic exacerbations
Asthma Episodic dyspnea, cough, and/or wheezing
Nocturnal symptoms
May have environmental trigger(s)
Bronchiectasis Chronic cough and purulent sputum production
Hemoptysis
Cystic fibrosis Sinusitis, bronchiectasis, meconium ileus, malabsorp-
tion, infertility (in males, congenital absence of vas
deferens)
Bronchiolar disorders Progressive dyspnea
Possible history of connective tissue disease,
inflammatory bowel disease, lung transplantation,
or hematopoietic stem cell transplantation
CVID, Common variable immunodeficiency; Dlco, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 second; FVC, forced
vital capacity; HRCT, high-resolution computed tomography.
FEV1/FVC <0.70 after bronchodilator use
Often reduced Dlco
Variable airflow obstruction on spirometry
Typically significant improvement in FEV1 with bron-
chodilator use
Dlco normal or elevated
Methacholine challenge shows airway hyperreactivity
Chest radiograph: “tram track” shadows
HRCT: dilated bronchi bigger than accompanying
vessel, lack of tapering of bronchi, visible bronchi
within 1-2 cm of lung border
Sputum culture may grow Haemophilus influenzae,
Pseudomonas aeruginosa, or atypical mycobac-
teria
Laboratory evaluation may reveal specific etiology
(e.g., decreased immunoglobulin levels in CVID)
Increased sweat chloride concentration, mutation in
CFTR chloride channel, elevated fecal fat, abnormal
nasal mucosal potential difference
Fixed airflow obstruction on spirometry
HRCT: mosaic attenuation pattern; centrilobular
nodules; tree-in-bud opacities
There are two major consequences of the changes in lung volume in obstructive lung disease. First, breathing at higher lung
volumes requires a higher change in pressure to achieve a smaller
change in lung volume, and this requirement increases the work
of breathing. Second, larger lung volumes place the inspiratory
muscles at a mechanical disadvantage. The diaphragm is flattened,
decreasing its ability to change intrathoracic volume, and all the
inspiratory muscle fibers are shortened, decreasing the tension they
are able to exert to effect changes in lung volume. The combination of a higher work of breathing and mechanical disadvantages
of the respiratory muscles caused by lung hyperinflation can lead
to respiratory muscle fatigue and failure in the setting of an abrupt
worsening of airway obstruction, as during an acute exacerbation
of COPD or asthma.
In addition to the clinical history and physical examination,
spirometry is a key step in the diagnostic work-up for a patient
with suspected obstructive lung disease. Although spirometry is
readily available and inexpensive, it is often underutilized, and
as a consequence, obstructive lung diseases are underdiagnosed.
Assessment of the clinical and spirometric response to a bronchodilator is a simple and helpful step in distinguishing asthma from
COPD. Measurement of the diffusing capacity of the lungs for carbon monoxide (Dlco) can also be helpful in separating asthma,
which is characterized by a normal or elevated diffusing capacity,
from COPD in which the diffusing capacity is often reduced by loss
of surface area for gas exchange. More sophisticated testing, such
as high-resolution chest computed tomography (HRCT), may be
needed to help diagnose less common causes of obstructive lung
disease (e.g., bronchiectasis).
The clinical features and laboratory findings associated with the
various obstructive lung disorders are summarized in Table 16.1.
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Definition and Epidemiology
The Global Initiative for Chronic Obstructive Lung Disease (GOLD)
currently defines COPD as a common preventable and treatable disease characterized by persistent airflow limitation that is usually
progressive and associated with an enhanced chronic inflammatory
response in the airways and lungs to noxious particles and gases. The
presence of airflow limitation is established by spirometry: If the ratio
of the forced expired volume in 1 second (FEV1) to the forced vital
capacity (FVC) is less than 0.70 after administration of a bronchodilator, airway obstruction is indicated. Although in the past COPD was
defined by the presence of either emphysema (a pathologic enlargement of the distal air spaces) or chronic bronchitis (a clinical syndrome
characterized by the presence of cough and sputum production for at
least 3 months in each of 2 consecutive years), the current definition is
based on the presence of airflow limitation and not on the presence of
these entities. Both emphysema and chronic bronchitis may occur with
or without the simultaneous presence of expiratory airflow limitation,
and therefore these entities overlap with but are not synonymous with
COPD. The current definition of COPD highlights the presence of persistent, reproducible expiratory airflow limitation and emphasizes the
progressive nature of COPD and the presence of abnormal inflammation in the lungs and airways.
COPD is a common disorder in populations across the world. The
Burden of Obstructive Lung Disease study, in a sample of adults from
12 countries, found that 10.1% had at least moderate airway obstruction (FEV1/FVC <0.70 and FEV1 <80% predicted) after administration
of a bronchodilator. Prevalence rates for COPD are correlated with
increasing age, lower socioeconomic status, and smoking. Although
COPD is more prevalent in men than in women, the prevalence of
CHAPTER 16 Obstructive Lung Diseases
100
FEV
(% of value at age 25)
Age (yr)
187
75
50
25
1
0
25
Fig. 16.2 Pattern of decline in forced expiratory volume in 1 second
(FEV1) with risks for morbidity and mortality from respiratory disease in
a susceptible smoker compared with a normal patient and with a nonsusceptible smoker. Although cessation of smoking does not replenish
the lung function already lost in a susceptible smoker, it decreases the
rate of further decline. (Data from Fletcher C, Peto R: The natural history
of chronic airflow obstruction, BMJ 1:1645-1648, 1977.)
COPD in women has been increasing, and annual death rates for
COPD have been steadily rising in both white and black women in
the United States. COPD results in a significant economic burden
in terms of health care expenditures and disability. In 2014, COPD
accounted for 44.3 per 100,000 deaths in the United States. According
to the World Health Organization, COPD is the fourth leading cause
of death worldwide.
COPD is a complex disorder that results from a susceptibility to
environmental factors brought about by a genetic predisposition.
Cigarette smoking is the major environmental cause of COPD,
although other factors may contribute, including outdoor air pollution, dust and fume exposure in the workplace, and indoor air pollution from use of biomass fuels for cooking and heat. Nonsmokers
can and do develop COPD, highlighting the role of non–tobaccorelated risk factors. A genetic predisposition is implied by the documentation of familial clusters of COPD. However, the only genetic
disorder thus far definitively linked to COPD is α1-antitrypsin deficiency resulting from mutations in SERPINA1, which accounts for
approximately 1% to 2% of all COPD cases. Recent studies have
highlighted other areas of the genome that are also associated with
COPD susceptibility.
Several longitudinal studies have defined patterns of age-related
decline in lung function and have documented the concept of age-related susceptibility to COPD. These studies showed that most adult
nonsmoking men exhibit a decline in FEV1 of 35 to 40 mL/year.
This rate is increased to 45 to 60 mL/year in most cigarette smokers.
However, the susceptible smoker may demonstrate losses of 70 to 120
mL/year (Fig. 16.2). This information allows the physician to project
the rate of decrease of lung function in patients with COPD and to
assess the effects of therapeutic interventions.
Pathology
Various structural changes have been observed in the airways and
lungs of individuals with COPD. The current definition of COPD
emphasizes the central role of chronic inflammation in the pathogenesis of COPD and in the development of pathologic lung and airway
remodeling in the setting of COPD. Structural changes observed in
COPD include emphysema and abnormalities of the small and large
airways. There is increasing evidence that the small airways are the
major site of airflow limitation and a central focus of pathology in
COPD.
Smoked regularly
and susceptible
to its effects
Disability
Death
Never smoked or not
susceptible to smoke
Stopped at 45
50 75
Stopped at 65
Emphysema in COPD
Emphysema is defined as a permanent enlargement of the air spaces
distal to the terminal bronchioles (E-Fig. 16.1). This is caused by
destruction of the lung parenchyma in the absence of significant fibrosis. These changes result in an abnormal acinus with limited capabilities for gas exchange. Based on thin gross lung sections, emphysema
can be classified as either centrilobular or panlobular (E-Figs. 16.2
and 16.3). In centrilobular emphysema, the proximal part of the lobule
(the respiratory bronchiole) is affected; this is the most common histologic feature observed in emphysema related to smoking. Panlobular
emphysema is seen in α1-antitrypsin deficiency.
α1-Antitrypsin is a serine protease inhibitor that deactivates elastase
molecules released by inflammatory cells that are capable of degrading
connective tissue matrices. The observations that this enzyme was associated with emphysema and that emphysema could be reproduced in
experimental models by the instillation of papain (a protease) into the
lungs led to the hypothesis that emphysema is caused by an imbalance
between protease and antiprotease systems in the lung. This theorized
imbalance would favor proteolytic destruction of lung connective tissue, resulting in emphysema (the protease-antiprotease hypothesis).
Research has focused on neutrophil elastase and its role in the destruction of lung elastin. Neutrophil elastase is the main target for inactivation by α1-antitrypsin and has relatively unopposed effects. However,
evidence for a primary role of this enzyme in cigarette smoke–induced
emphysema is less clear, so the focus has broadened to include examination of the role of the matrix metalloproteinases (MMPs), produced
by macrophages and other cells, in emphysema.
The inflammation induced by cigarette smoke is a trigger of the
cycle of protease release and lung destruction resulting in emphysema (E-Fig. 16.4). Macrophages are activated by cigarette smoke and
recruit neutrophils and other inflammatory cells to the lung, leading to
the release of elastase and MMPs. The destruction of elastin and other
connective tissue elements in the lungs by these proteases leads over
time to the loss of elastic recoil and destruction of alveolar structures
characteristic of emphysema.
Cigarette smoke contains many oxidant molecules capable of
inducing oxidative stress in the lung. Oxidative stress has diverse
effects, including the oxidative inactivation of antiproteases in the
lung and the acetylation of specific histones in the chromatin of lung
cells and macrophages, allowing the expression of various pro-inflammatory genes. Histone deacetylase activity is reduced in COPD, and
this in turn may result in an inability to control the pro-inflammatory response in this condition. Pro-inflammatory gene expression
promotes cytokine production and release, contributing to further
inflammatory cell recruitment and activation. Systemic inflammation,
triggered by ongoing pulmonary inflammation, may lead to nonpulmonary abnormalities associated with emphysema, including cachexia
and skeletal muscle alterations. Finally, increased apoptosis of pneumocytes and endothelial cells has been observed in lungs with emphysema and could contribute to the loss of alveoli.
Understanding of emphysema pathogenesis has improved with the
recognition that inflammation, oxidative stress, protease-antiprotease
balance, and apoptosis are linked in a complex interaction induced
by cigarette smoke. This improved understanding has broadened the
range of potential therapies that may be effective in ameliorating the
destructive process. To date, however, therapies targeted at molecular
pathways involved in emphysema pathogenesis have not been successful in altering disease progression, with the possible exception of
α1-antitrypsin replacement therapy in individuals with α1-antitrypsin
deficiency.
α1-Antitrypsin, an acute phase reactant, is produced primarily in
the liver, from which it travels to the lung. By its effect on elastases
CHAPTER 16 Obstructive Lung Diseases
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187.e1
E-Fig. 16.1 Emphysema with enlargement of distal air spaces. (Cour-
tesy Dr. Charles Kuhn.)
E-Fig. 16.3 Panlobular emphysema. Emphysema extends to edge of
lobules. (Courtesy Dr. Charles Kuhn.)
E-Fig. 16.2 Centrilobular emphysema surrounded by normal lung.
(Courtesy Dr. Charles Kuhn.)
Cigarette smoke
and
Radical
oxygen
species
Inactivation
of protease
inhibitors
Lung
tissue
destruction
Macrophage
activation
Release
of cytokines and
growth factors
Inflammation
Edema
Immune cell
recruitment
E-Fig. 16.4 Mechanisms of cigarette smoke–induced inflammation and
oxidant injury. MMPs, Matrix metalloproteinases.
Elastases
MMPs
Neutrophil
activation
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