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How are obstructive lung diseases characterized? How do they arise? What are some causes? What diseases are included in COPDs? How are they related to each other?

Obstructive lung diseases are characterized by reductions in
airfl ow due to increased resistance from partial or complete
airway obstructions at any level. Such obstructions can arise
from direct narrowing of the airway lumen or by decreased
elastic recoil of the pulmonary parenchyma surrounding the
airways, which has the effect of reducing lumen caliber. The
many causes of obstructive disease include tumors, aspirated
foreign bodies, asthma, emphysema, chronic bronchitis, cystic
fi brosis, and bronchiolitis. This chapter will focus on the
pathology of emphysema, chronic bronchitis, asthma, and
bronchiectasis. Bronchiectasis is included here although it
occurs as a result of airway obstruction, rather than being a cause
in itself. The chronic obstructive pulmonary diseases (COPDs)
comprise emphysema and chronic bronchitis. Though it is possible
to have emphysema without chronic bronchitis or the converse,
most patients have some degree of both, though one may
dominate the clinical scenario. They share common etiologies,
the most signifi cant of which is tobacco smoking. Despite this
signifi cant association, most smokers do not develop COPD.


Define emphysema. How common is it? What are the four types?

Emphysema is defi ned morphologically as the irreversible enlargement
of airspaces distal to the terminal bronchioles, due to destruction
of airspace walls and without obvious fi brosis. Emphysema
is present in approximately one-half of adults at autopsy, most
of whom were asymptomatic. Emphysema is further subdivided
into four subtypes based on the anatomic distribution of the
airspace enlargement: centriacinar (centrilobular), panacinar
(panlobular), distal acinar (paraseptal), and irregular.


How is centriacinar emphysema characterized? What is an alternate name? Why does it have the alternate name? How common is it? What is it associated with? Where is it most pronounced?

Centriacinar emphysema (Figs. 20.1 and 20.2) is characterized
by airspace enlargement at the level of the respiratory
bronchioles, sparing the distal alveoli. Anatomically, the several
acini that comprise a lobule (Chap. 2) are arranged such
that their respiratory bronchioles are grouped in the center of
the lobule. This anatomic arrangement underlies the alternate
name, centrilobular emphysema. Centriacinar emphysema
accounts for more than 95% of those cases of emphysema with clinically signifi cant airway obstruction. It is more pronounced
in the upper lobes and is the type of emphysema most
strongly associated with smoking.


How is panacinar emphysema characterized? What is an alternate name? Explain it. How common is it? Where is it more pronounced? What is it associated with?

Panacinar emphysema (Figs. 20.1 and 20.3) is characterized
by airspace enlargement at the level of the alveolar ducts
and more distally. At the gross level, airspace enlargement
appears to affect the entire lobule, giving rise to the alternate
name, panlobular emphysema. Panacinar emphysema
accounts for less than 5% of cases of emphysema with clinically
signifi cant airway obstruction and is more pronounced
in the lower lung zones. It is the type of emphysema most
strongly associated with α1-antiprotease (α1-PI) defi ciency
(Chap. 22).


How is distal acinar emphysema characterized? Where is it most prominent? What are its clinical results? Where is it more severe?

Distal acinar emphysema (Fig. 20.4) involves distal airspaces
and is most prominent adjacent to the visceral pleura
and to the connective tissue septa that defi ne the lobules. Distal
acinar emphysema typically does not result in clinically
signifi cant airway obstruction. It is more severe in the upper
half of the lungs and likely represents the underlying lesion
resulting in spontaneous pneumothorax in young adults.


Describe irregular emphysema. What is it like clinically? Define bullous emphysema.

Emphysema that does not show centriacinar, panacinar, or
distal acinar distribution is called irregular emphysema. Irregular
emphysema is very common adjacent to foci of scarring
and does not typically cause signifi cant airway obstruction. In
any form of emphysema, large, distended sacs of air or bullae
can form. Any subtype of emphysema with bullae is likely to
be referred to as bullous emphysema (Fig. 20.5). In its most
severe forms, emphysema is diffi cult to subclassify (Fig. 20.6).


Describe the pathogenesis of emphysema.

The pathogenesis of emphysema is generally considered
to involve excess protease and/or elastase activity that is
insuffi ciently opposed by antiprotease regulation (Fig. 20.7).
The probable sequence begins with neutrophil sequestration
in capillaries, migration into airways and alveoli, and their stimulation to release elastase-containing granules that
degrade elastic tissue in the absence of suffi cient antiprotease
activity (Chap. 10). Such antiprotease insuffi ciency can be due
to α1-PI defi ciency and/or the functional impairment of it and
other antiproteases (Chap. 22).

Compared with nonsmokers, the parenchyma of current
smokers contains more alveolar macrophages and alveolar
neutrophils. Smoking stimulates release of elastase and
other proteases from neutrophils. Tobacco smoke also
enhances macrophage elastase activity that is not inhibited
by α1-PI, and indeed it may degrade α1-PI. The activity of
α1-PI is further blunted by the oxidants and free radicals in
smoke, as well as similar oxidants secreted by neutrophils.

Given that emphysema involves tissue destruction and
enlargement of airspaces, it may seem counterintuitive that
affected individuals exhibit signifi cant airfl ow obstruction by
PFT (Chaps. 16 and 22). This obstructive pattern emerges in
emphysema due to the loss of lung parenchyma, whose elastic
recoil normally tethers the airways open by radial traction
forces (Chaps. 5 and 6). In the absence of such radial tethering,
the airways open less widely during inspiration, and they
also collapse more readily during expiration.


Describe compensatory emphysema, mediastinal emphysema, interstitial emphysema, subcutaneous emphysema, obstructive overinflation, and congenital lobar emphysema.

Rather unfortunately, the term “emphysema” has been
applied to other medical conditions that technically do
not satisfy the defi nition used here of irreversible airspace
enlargement caused by tissue destruction. By example, compensatory
emphysema is used to describe the excessive dilatation
of residual alveoli following loss of lung volume as by
lobectomy. In that setting, since there has been no destruction
of airspace walls, the preferred term is compensatory
hyperinfl ation. The terms mediastinal emphysema, interstitial
emphysema, and subcutaneous emphysema all can refer
to the presence of air within connective tissue spaces that
normally contain none. In the chest and neck, this is most
typically due to a perforated airway lining, as can occur
by faulty intubation for mechanical ventilation (Chap. 30),
with subsequent dissection or insuffl ation of air through the
adjacent adventitial layers. Obstructive overinfl ation can
mimic emphysema on gross examination and is occasionally
called emphysema, again despite the absence of airspace
wall destruction. Obstructive overinfl ation of airways
occurs when obstructions such as mucus or tumor mass act
as a ball-valve, allowing airfl ow during inspiration but not
on expiration. With severe or total airway obstruction, air
may move through collateral septal pathways (pores of Kohn
and canals of Lambert) more readily during inspiration than
expiration, causing alveolar overinfl ation. A classic form of
such obstructive overinfl ation occurs in congenital lobar
emphysema (also termed infantile lobar overinfl ation) as
discussed in Chap. 37.


Define chronic bronchitis. Define the 3 different types.

In contrast to emphysema, chronic bronchitis is defi ned not
morphologically but clinically as a persistent, productive cough
for at least three consecutive months in at least two consecutive
years and without another identifi able cause (Chap. 22).

Among the 5%-15% of smokers who develop physiological
evidence of COPD by PFT work-ups, many of those have an
initial clinical presentation that includes chronic bronchitis.
As such, chronic bronchitis is subdivided into three subtypes:
simple chronic bronchitis, in which there is no PFT-based evidence
of obstruction; obstructive chronic bronchitis, in which there is physiological evidence of obstruction; and chronic
asthmatic bronchitis, in which a patient’s hyper-responsiveness
to allergens or other stimuli contributes to the airway
obstruction (Chaps. 21 and 22).


Describe the pathogenesis of chronic bronchitis.

The pathogenesis of chronic bronchitis begins with inhalation
of smoke and/or other air pollutants, resulting in hypersecretion
of mucus by bronchial mucous glands, hyperplasia
of mucous glands, and goblet cell metaplasia (Chap. 2).
Excessive mucus worsens airway obstruction and increases the
susceptibility to infection, resulting in infl ammation, fi brosis,
and subsequent narrowing of bronchioles. Further increasing
the likelihood of infection is the impairment of mucociliary
clearance (Chap. 10) caused by smoke-induced ciliary dysfunction
and/or by squamous metaplasia of the airway lining.


Where is the obstruction in simple chronic bronchitis? What is the usual cause of obstruction in chronic bronchitis if the obstruction is moderate to severe? Describe chronic bronchitis both grossly and microscopically.

In COPD patients with simple chronic bronchitis, obstruction
is mainly within respiratory bronchioles. In patients with
moderate or severe obstruction, most of their diminished fl ow
by PFT is due to superimposed emphysema. Grossly, chronic
bronchitis shows mucosal hyperemia, edema of large airways,
and mucinous or mucopurulent intraluminal secretions in large
and small airways. Microscopically, mucous gland hyperplasia
in the trachea and large bronchi is frequently accompanied by
goblet cell hyperplasia and/or loss of cilia. Collectively these
thicken the mucous gland layer.


What is the reid index? Normal values?

The Reid Index is a morphologic measurement of the
severity of chronic bronchitis and is defi ned as the ratio
of mucous gland thickness to the distance between
epithelium and cartilage, both measured radially on
airways viewed in histological cross-section. The Reid
Index is normally about 0.4 in lungs from asymptomatic
nonsmokers but increases dramatically with the severity of
chronic bronchitis (Fig. 20.8).


Does chronic bronchitis always show inflammation? Explain. Describe small airway disease. What is bronchiolitis obliterans?

Chronic bronchitis, despite its suffi x, does not always
show severe infl ammation. In the absence of superimposed
infection, the infl ammatory infi ltrate is predominantly mononuclear
(Fig. 20.9) as would be expected based on normal
lung host defense mechanisms (Chap. 10). When superimposed
infection is present, variable numbers of neutrophils are likely.
In the setting of chronic bronchitis, there is typically small
airway disease (chronic bronchiolitis) featuring goblet cell
metaplasia, infl ammation, smooth muscle hyperplasia, thickened
basement membranes, and fi brosis. In the most severe forms, the fi brosis occludes the bronchiolar lumen to cause
bronchiolitis obliterans.


How is asthma characterized? How is it classified? What can complicate it? What is this called?

Asthma is a chronic infl ammatory airway disease characterized
by episodic bronchospasm which is clinically manifest as
an asthma attack comprising dyspnea, chest tightness, cough,
and wheezing (Chap. 21). The airway luminal narrowing is
partially reversible, and infl ammation likely plays a role in causing exaggerated bronchoconstriction. Asthma affects
approximately 5% of adults and 7%-10% of children in the
United States. There are several approaches to classifying
asthma (Table 20.1); regardless of the system used, many
patients will have features overlapping two or more categories
(Chap. 21). Asthma can be complicated by Aspergillus ssp.
colonization of the bronchial mucosa which, in a patient with
allergy to the fungus, is called allergic bronchopulmonary


Describe the pathogenesis of asthma.

Main factors underlying the pathogenesis of asthma are
a genetic predisposition to type I hypersensitivity reactions,
airway infl ammation, and bronchial hyperresponsiveness.
Many infl ammatory cells play roles in the pathogenesis of
asthma: eosinophils, mast cells, macrophages, neutrophils,
and lymphocytes. Among these lymphocytes, the CD4+ T-cells
include TH1 and TH2 phenotypes. A number of TH1-derived
cytokines (eg, IFN-γ, IL-2) activate macrophages and CD8+
cytotoxic T-cells to kill viruses and other intracellular pathogens.
TH1 cells also inhibit the action of TH2 cells. In contrast,
the TH2-derived mediators promote allergic infl ammation and
stimulate production of IgE by B-cells. Additionally, TH2 cells
inhibit TH1 cells. In asthma, it appears that this mutual inhibition
of TH1 cells and TH2 cells is altered to favor TH2 cellmediated
effects. The transcription factor T-bet that is required
for TH1 cell differentiation has been found to be diminished or
lacking in pulmonary lymphocytes in the setting of asthma.
Thus, a future approach to asthma may be to up-regulate T-bet
expression (Chap. 21). Despite the role of lymphocytes in the
pathogenesis of asthma, the infl ammatory infi ltrate in asthma
is typically rich in eosinophils.


How is asthma defined morphologically? What causes this to happen?

Morphologically, asthma is characterized by airway
remodeling, including bronchial smooth muscle hypertrophy
and subepithelial collagen deposition. Recently, the gene
ADAM-33 that encodes a metalloproteinase has been linked
to asthma. Polymorphisms in ADAM-33 accelerate bronchial
smooth muscle cell proliferation, resulting in bronchial hyperreactivity,
and accelerate fi broblast proliferation, leading to
subepithelial fi brosis.


What are some forms of extrinsic asthma? Explain the pathophysiology of it?

Pathogenetically, asthma can be subdivided into extrinsic
and intrinsic categories. All forms of extrinsic asthma
involve initiation of an asthmatic crisis by a type I hypersensitivity
reaction to an extrinsic antigen, which in this setting
can be called an allergen. The most common form of
extrinsic asthma is atopic asthma; other forms of extrinsic
asthma include some types of occupational asthma as well as allergic bronchopulmonary aspergillosis. Sensitization
occurs when inhaled allergens stimulate an infl ammatory
response dominated by TH2 cells, favoring the production of
IgE and recruiting eosinophils. The IgE released by B-cells
attaches to the surface of resident mast cells. Once sensitized,
reexposure to the allergen can trigger the asthma attack, classically
described as having an early phase and late phase.
The early phase occurs 30-60 minutes after exposure as the
inhaled antigen binds to IgE on mast cells, stimulating release
of their mediators that cause bronchoconstriction, edema,
mucus secretion, and recruitment of granulocytes, especially
eosinophils. The late phase begins 4-8 hours after the
early phase and is dominated by eosinophil release of mediators
that activate mast cells. During the late phase, these
eosinophil-derived mediators increase and sustain the infl ammatory
response that damages airway epithelia, even in the
absence of additional allergen exposure. If exposure persists,
the epithelial injury facilitates translocation of inhaled allergen
from the airway lumen into the subepithelial connective
tissue, where more infl ammatory cells reside.


What is intrinsic asthma? Describe a couple forms of it. Describe it clinically?

Intrinsic asthma involves nonimmune triggers of an
asthma attack. Its subtypes include non-atopic asthma that
is usually initiated by viral respiratory infections. The ensuing
infectious infl ammation stimulates subepithelial vagus
receptors, causing bronchospasm. A classic example of druginduced
asthma is initiated by aspirin, in which cyclooxygenase
inhibition leads to leukotriene synthesis that stimulates

Intrinsic asthma can be triggered by aspirin, viral infection,
inhalation of cold air or chemical irritants, psychological
stimuli including stress, and exercise. Notably, triggers
of intrinsic asthma also cause bronchospasm in nonasthmatics,
and bronchospasms in intrinsic asthma are
more pronounced and persistent than those associated
with extrinsic asthma.


Describe asthma morphologically and microscopically.

Morphologically, asthma is characterized by bronchial
wall edema, erythema due to hyperemia, and infl ammation,
with 5%-50% eosinophils. These are accompanied by patchy epithelial necrosis and cell shedding, with basement membrane
thickening due to subepithelial deposition of collagen.
Hyperplasia of submucosal mucous glands and goblet cells is
evident, as well as hypertrophy and hyperplasia of bronchial
smooth muscle (Fig. 20.10).
Microscopic features of asthma overlap with those of
chronic bronchitis. Clues that help distinguish asthma from
chronic bronchitis morphologically include whorls of shed
epithelium termed Curschmann spirals, and eosinophildominant
infl ammation that produces Charcot-Leyden crystals
composed of eosinophil proteins (Fig. 20.11).


What does asthma look like clinically? What treatment is there? What is status asthmaticus and what does it lead to?

Clinically, the asthma attack includes wheezing and dyspnea,
with more diffi cult expiration. Symptoms can last several
hours and are followed by prolonged coughing. Though the
asthma attack can spontaneously resolve, medical therapy with
bronchodilators and/or corticosteroids can expedite resolution
(Chap. 21). In some patients, a severe and treatment-resistant
asthma attack can persist for days to weeks, resulting in status
asthmaticus and leading to hypoxemia, acidosis, and death. In
the event of such a death, autopsy would show plugging of airways
by viscous mucus.


Define bronchiecstasis. List various causes. What is the pathogenesis like?

Bronchiectasis is defi ned as the permanent dilatation of airways
due to the destruction of tissue caused by chronic necrotizing
infl ammation and obstruction (Fig. 20.12). Bronchiectasis
is not a primary disease but rather occurs secondarily to
chronic infection and/or chronic obstruction. There are many
predispositions to the development of bronchiectasis: bronchial
obstruction; congenital and hereditary conditions such
as cystic fi brosis, immunodefi ciency, ciliary dyskinesia, and
intralobar sequestration; necrotizing or suppurative pneumonia;
and allergic bronchopulmonary aspergillosis. The pathogenesis
of bronchiectasis involves obstruction and persistent
infection, occurring in either order and frequently overlapping.
The infection usually involves mixed fl ora.


What is bronchiecstasis like morphologically? Where is this more prominent? What can complicate bronchiecstasis?

Morphologically, there is by defi nition bronchial dilatation
up to fourfold normal airway diameters. Such bronchial
dilatation is usually more prominent in lower lung lobes and
can be cylindroid, fusiform, or saccular. In the setting of
active infection, there is typically a dense mixed infl ammatory
exudate with epithelial ulceration. The chronic nature of
the infl ammation is refl ected in bronchial, bronchiolar, and
peribronchial fi brosis. Bronchiectasis can be complicated by
abscess formation.


What is the presentation like in bronchiecstasis?

Clinically, the patient with bronchiectasis
presents with severe, persistent cough and mucopurulent sputum that is occasionally bloody. Additional clinical fi ndings
may include frank hemoptysis, digital clubbing, and the
blood gas sequelae expected with pulmonary obstruction as
well as disseminated infection and reactive amyloidosis.