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What is atelectasis? What are some possible results of it? Describe four different types of atelectasis. What causes each to occur? Which ones are reversible? Which way does the mediastinum shift in each?

Atelectasis describes a reduction in lung volume due to incomplete
expansion of airspaces or, more commonly, the collapse
of previously inflated pulmonary parenchyma. In atelectasis,
perfusion of such nonventilated lung creates a physiological
shunt that mixes inadequately oxygenated blood from pulmonary
arteries with better oxygenated blood in the pulmonary
veins (Chap. 9). If the ventilation-perfusion mismatch is sufficiently
severe, systemic hypoxemia results. Additionally,
atelectatic lung is more likely to become infected.

Atelectasis can be subdivided by its pathogenesis.
In resorption atelectasis (also known as obstruction
atelectasis), air is prevented from reaching distal airspaces
because of airway obstruction. Then, as more distal
air is absorbed, the previously expanded lung collapses. The
extent of involvement is determined by the level of obstruction:
Obstruction of a major airway can result in collapse of
an entire lobe. Most commonly, a mucous or mucopurulent
plug is responsible for the obstruction, although any physical
obstruction will suffice. In resorption atelectasis, the mediastinum
shifts toward the affected side.

In compression atelectasis (also known as passive
atelectasis and as relaxation atelectasis), accumulation of
space-occupying material within the pleural space mechanically
compresses the lung parenchyma (Fig. 26.1). Compression
atelectasis complicates pleural effusion and pneumothorax
(see below), as well as pleural tumors (Chap. 31). Additionally,
compression atelectasis of basal lung zones complicates peritoneal
effusion (ascites) and frequently occurs in bedridden
patients due to diaphragmatic elevation. In compression
atelectasis, the mediastinum shifts away from the affected side.

Microatelectasis complicates adult and neonatal respiratory
distress syndromes (Chaps. 23 and 39) as well as interstitial
inflammatory lung diseases (Chap. 23). Its pathogenesis
involves a complex set of events, the most important being
deactivation of surfactant in the mature lung or its inadequate
synthesis in neonatal lung.

In the setting of localized or generalized pulmonary
fibrosis, the foci of fibrosis contract largely due to the action of myofibroblasts, collapsing adjacent lung tissue and resulting in contraction atelectasis or cicatrization atelectasis.

Generally, resorption atelectasis, compression atelectasis,
and microatelectasis are reversible, while contraction atelectasis
is not.


What is pulmonary edema? Generally, what causes it? List some specific causes as well as how common they are.

When edema develops in the lung, the excess fluid rapidly
moves from the interstitium to the airspaces (Chaps. 7 and 28).
While there are many specific causes of pulmonary edema
(see Table 7.2), it is generally due to a change in hemodynamics
(perfusion vs interstitial pressures) or to microvascular injury.
Congestive heart failure is the most common cause of an
increase in pulmonary venous pressure and the resultant pulmonary
edema. Less commonly, reduction of plasma oncotic
pressure will result in egress of fluid from the vascular space
into the interstitium and then the alveoli. Alternatively, an
increase in the permeability of capillaries, as occurs in the setting
of alveolar and microvascular injury, can result in edema
(Chap. 28).


Describe the gross and microscopic histology of pulmonary edema. What differences are there when it is due to elevated pulmonary venous pressure?

Gross manifestations of pulmonary edema include increase
in lung weight and a wet cut surface with frothy fluid visible
in larger airways. Microscopically, pulmonary edema is
characterized by pale, eosinophilic, glassy or finely granular intra-alveolar precipitate [Fig. 26.2 (a)]. In the setting of pulmonary
edema secondary to elevation of venous pressure,
alveolar septal capillaries will show congestion characterized
by engorgement with blood. Due to the delicate nature of alveolar
septa, congestion is typically accompanied by occasional rupture of capillaries, resulting in microhemorrhages that
release formed blood elements into alveolar spaces. As erythrocytes
are cleared by macrophages, hemoglobin is progressively
catabolized to hemosiderin, which persists in macrophage
cytoplasm. Thus, the presence of hemosiderin-laden macrophages
(or siderophages) reflects remote hemorrhage and
implies chronic congestion [Fig. 26.2 (b)]. While any form
of pulmonary hemorrhage will eventually show siderophages,
the most common cause of pulmonary congestion and hemorrhage
is congestive heart failure. This has led to widespread
usage of the term “heart failure cells” to describe such intraalveolar
hemosiderin-laden macrophages.


What are is pulmonary embolus? What is the most common cause? What are some risk factors for this?

A large majority of pulmonary emboli are thrombotic in origin.
Therefore, unless otherwise specified, the term “pulmonary
embolus” typically refers to pulmonary thromboembolus.
Pulmonary thromboembolism is involved in approximately
10% of hospital deaths. In more than 95% of cases, the source
of pulmonary thromboemboli is a thrombus in a deep vein of
the lower extremity (Chap. 27). Risk factors for venous thrombosis
and pulmonary thromboembolus include prolonged bed
rest (especially in the setting of lower extremity immobilization),
severe trauma, burns, congestive heart failure, and
hypercoagulable states (Table 26.1).


What are some primary causes of hypercoagulable states? Secondary causes?


Antithrombin III defi ciency
Protein C defi ciency
Defective fi brinolysis
Factor V Leiden
Prothrombin 20210A
Antiphospholipid syndrome


Recent surgery
Oral contraceptive with high estrogen content


Describe how a pulmonary thromboembolus proceeds and what its complications are.

When a venous thrombus embolizes, it travels in progressively
larger systemic veins toward the right heart. Upon
ejection from the right ventricle, fragments of the embolism move into progressively smaller branches of the pulmonary
artery until they reach vessels too small to allow passage. At
that point the thromboemboli occlude a pulmonary artery
or arteriole and increase pulmonary vascular resistance and
can induce vasospasm. When a major vessel is occluded, the
resulting pulmonary hypertension can reduce cardiac output
and induce cor pulmonale and death. If death does not
result, pulmonary thromboembolism results in hypoxemia
due to ventilation-perfusion mismatch with increased dead
space ventilation (Chap. 8). The ischemia may also reduce
surfactant release and cause pleuritic pain that add to the work
of breathing (Chaps. 5 and 6). Despite the lung’s systemic
blood supply (Chap. 2), pulmonary thromboembolism can
result in lung parenchymal ischemia and pulmonary infarction.
In patients with patent foramen ovale (~30% of all people), pulmonary arterial thrombotic occlusion can cause
right-to-left shunting and subsequent paradoxic embolism,
in which a venous thrombus enters and embolizes systemic
arteries and cause distal ischemia.


What is the gross appearance of a thromboembolus? Microscopic? What is the gross appearance of a lung infarct? Microscopic?

Grossly, a pulmonary thromboembolus is a serpentine blood
clot impacted in a pulmonary arterial branch [Fig. 26.3 (a)].
A very large thromboembolus occluding the main pulmonary
arteries is typically referred to as a “saddle embolus.” Microscopically,
the thromboembolus is characterized by alternating
layers of fibrin (eosinophilic) and erythrocytes. Ischemic lung
damage is characterized by intra-alveolar hemorrhage [Fig.
26.3 (b)]. A pulmonary infarct will be conical (or, on cut section,
wedge-shaped) and hemorrhagic [Fig. 26.4 (a)]. Initially,
the infarct is red-blue. It becomes paler and later red-brown as
erythrocytes lyse and hemoglobin is degraded to hemosiderin.
Next, as fibroblasts progressively replace necrotic tissue with
scar, the infarct shows a gray-white peripheral zone. Microscopically,
infarcted lung tissue shows coagulative necrosis
with loss of nuclear basophilia, although alveolar hemorrhage
often dominates the microscopic appearance [Fig. 26.4 (b),
(c)]. In cases of sudden death due to saddle embolus, there are
typically no gross or microscopic changes to the lung.


Clinically, what happens with pulmonary emboli? What is the risk of a recurring pulmonary embolism? What can they result in? How are pulmonary embolisms treated?

Clinically, 60%-80% of pulmonary thromboemboli are
asymptomatic; approximately 5% cause acute cor pulmonale,
shock, or sudden death; and 10%-15% affect medium-sized
arteries and, through an unknown mechanism, cause dyspnea.
In the presence of an underlying risk factor, a patient who
has had pulmonary thromboembolism has a 30% chance of
recurrent pulmonary thromboembolism. A minority (< 3% of
patients with recurrent pulmonary thromboembolism develop pulmonary
hypertension (see below), chronic cor pulmonale, vascular sclerosis, and worsening dyspnea. Treatment of pulmonary
thromboembolism involves thrombolysis and anticoagulation.
If anticoagulation is contraindicated or not sufficient, a
filter (Greenfield filter, umbrella) can be placed in the inferior
vena cava; thromboemboli caught in the filter will undergo


Aside from thrombi, what are some other causes of pulmonary embolisms? What are the effects?

In addition to venous thrombi, the student should remember
that embolism of the lung can be caused by air, bone marrow,
fat, foreign bodies, and amniotic fluid. In most instances,
the hemodynamic effects from such materials resemble those
caused by thrombi (Chap. 27). However, the duration of such
effects and the severity of pulmonary compromise they cause
may be transient (as for the nitrogen in air), or may persist
(as has been noted for crystals of talcum used to “cut” certain
drugs before their intravenous abuse). Amniotic fluid embolism
is a devastating event, often resulting in maternal death
in the peripartum period.


Define pulmonary hypertension. What are the general causes? How common are they?

Normally, pulmonary arterial pressure is approximately oneeighth
that of systemic arterial pressure. Pulmonary hypertension
is defined as a pulmonary arterial blood pressure
greater than or equal to one-fourth systemic arterial blood
pressure. Pulmonary hypertension can be a primary disorder
or a disorder secondary to an underlying condition. Primary
pulmonary hypertension is less common than secondary forms
and is typically sporadic, though familial forms exist.


What is BMPR2 and what does it do? How does it lead to pulmonary hypertension?

In some cases of primary pulmonary hypertension, the
pathogenesis involves a mutation in the gene encoding bone
morphogenetic protein receptor type 2 (BMPR2), a cell
surface protein (in the TGF-β superfamily) that binds many cytokines (including TGF-β, BMP, activin, and inhibin). In
vascular smooth muscle cells of the tunica media, normal
BMPR2 signaling decreases proliferation and increases apoptosis.
An inactivating mutation of the BMPR2 gene, thus,
results in smooth muscle proliferation. Such a mutation is
present in approximately one-half of patients with familial primary
pulmonary hypertension and approximately one-fourth
of patients with sporadic primary pulmonary hypertension.


What occurs in secondary pulmonary hypertension? What are some causes?

In secondary pulmonary hypertension, endothelial cell
dysfunction results from increased shear and mechanical
force, due to increased flow and/or increased pressure, or from
biochemical injury (eg, due to effects of fibrin in the setting of
thromboembolism). Subsequent to endothelial injury, reduction
in prostacyclin and NO leads to pulmonary vasoconstriction,
platelet adhesion, and platelet activation, while various
growth factors and cytokines induce migration and replication
of vascular smooth muscle cells. Many conditions cause
increased pulmonary blood flow, increased pulmonary vascular
resistance, or increased left heart resistance to blood flow
and result in secondary pulmonary hypertension (Table 26.2).

Chronic obstructive lung disease
Congenital or acquired heart disease
Recurrent pulmonary emboli
Autoimmune disorders
Obstructive sleep apnea syndromes


What is the morphology of pulmonary hypertension in large, medium, and small arteries?

The morphology of pulmonary hypertension—primary
or secondary—is manifest throughout the pulmonary arterial
tree. Main elastic arteries develop atheromata; medium-sized
arteries develop hyperplasia of the tunica intima and the tunica
media, resulting in thickening of the arterial wall and luminal
stenosis (Fig. 26.5); small arteries and arterioles develop
medial hypertrophy with reduplication of elastic membranes.


How does primary pulmonary hypertension present? In whom does it normally present? How does secondary pulmonary hypertension present?

Clinically, primary pulmonary hypertension affects
young (20- to 40-year old) patients, more commonly women, and presents with fatigue, syncope (especially on exertion),
dyspnea on exertion, and chest pain. Eventually, patients
develop severe respiratory insufficiency and cyanosis, with
death within 2-5 years in more than three quarters of cases.
The clinical scenario in secondary pulmonary hypertension
varies by the underlying disease, though respiratory insufficiency
and right heart failure eventually develop.


Describe Goodpastures syndrome? What is it like epidemiologically? Pathogenitically? Grossly? Microscopically?

Goodpasture syndrome is an autoimmune disease characterized
by the simultaneous development of proliferative
glomerulonephritis (typically crescentic) and necrotizing,
hemorrhagic interstitial pneumonitis. Epidemiologically, it
is associated with certain HLA subtypes and shows a male
predominance; presentation is typically in the teens or twenties.
Pathogenetically, IgG autoantibodies are directed against an
epitope on the α3 chain of collagen IV. Collagen IV is nonfibrillar
and is a key component of basement membranes. The
autoantibody-induced basement membrane damage results in
clinically significant glomerular and pulmonary injury. With
respect to gross pulmonary disease, lungs are heavy, consolidated,
and discolored red-brown. Microscopically, the Goodpasture
syndrome lung shows focal alveolar wall necrosis with
intra-alveolar acute hemorrhage and alveolar septal fibrotic
thickening (Fig. 26.6).


How is Goodpasture diagnosed? What is its clinical presentation like? How is it treated?

In the setting of suspected Goodpasture syndrome,
immunofl uorescence analysis of lung and/or kidney can
be informative. In this disease, immunofl uorescent labeling
with IgG will show a linear basement membrane label
of alveoli (Fig. 26.7) and glomeruli, rather than a granular
basement membrane label typical of immune complex
deposition. Immunofl uorescence analysis requires frozen,
nonfi xed tissue. Consequently, in any situation in which
immunofl uorescence analysis would be helpful, it is
important to promptly deliver fresh tissue to the pathologist
to be frozen and sectioned for immunofl uorescence labeling
rather than placing the tissue in a fi xative (eg, 10% formalin),
as is typically done with biopsy specimens.

Clinically, the presentation of Goodpasture syndrome
typically involves hemoptysis with the subsequent development
of rapidly progressive renal insufficiency. Therapy
involves removal of the pathologic autoantibodies by plasmapheresis
and reduction of autoantibody production through


What is Wegener's granulomatosis? What is its pathophysiology? What is the clinical scenario? What is it like morphologically?

Wegener’s granulomatosis is a systemic vasculitis with
a peak incidence in the fifth decade. Pathogenetically, it is
likely a form of hypersensitivity, and patients typically have
anti-neutrophil cytoplasmic antibodies with cytoplasmic
localization (c-ANCA). Simplistically, the antibodies activate
neutrophils, which then attack vascular luminal surfaces,
resulting in vasculitis of small and medium-sized vessels. Like
Goodpasture syndrome, the clinical scenario in Wegener’s
granulomatosis is dominated by simultaneous pulmonary and
renal disease. Morphologically, respiratory tract involvement
in Wegener’s granulomatosis includes upper tract vasculitis, mucosal granulomata, and ulcers rimmed by granulomatous
inflammation as well as lower tract necrotizing granulomatous
inflammation (often with cavitation) and necrotizing or
granulomatous vasculitis (Fig. 26.8). Renal involvement is
typified by necrotizing glomerulonephritis, typically with
crescent formation (extracapillary proliferation).


How is idiopathic pulmonary hemosiderosis characterized? What is it like grossly? Microscopically? How is it diagnosed pathologically?

Idiopathic pulmonary hemosiderosis is a disease of
children and young adults characterized by the insidious
development of hemoptysis, anemia, and weight loss. Morphologically,
lungs are heavy, consolidated, and discolored
red to red-brown. Microscopically, lungs show alveolar epithelial degeneration, shedding, and hyperplasia; intra-alveolar
siderophages; marked congestion of alveolar septal capillaries;
and varying degrees of fibrosis.

 C L I N I C A L CO R R E L AT I O N 2 6 . 3
Figure 26.9 shows Prussian blue staining (Pearl
reaction, iron stain) of the cytospin preparation from
bronchoalveolar lavage fl uid in the setting of idiopathic
pulmonary hemosiderosis. Numerous hemosiderin-laden
macrophages are seen, from which the disease takes its
name. With this stain, hemosiderin is blue.


What are 6 drugs that induce pulmonary disease? What is the pathological type of disease caused by each?

Bleomycin Pneumonitis and fi brosis

Methotrexate Hypersensitivity pneumonitis

Amiodarone Pneumonitis and fi brosis

Nitrofurantoin Hypersensitivity pneumonitis

Aspirin Bronchospasm

β-Antagonists Bronchospasm


What kind of injury does ionizing radiation lead to in the lung? What is it like clinically (timeline)? Morphologically? What can this lead to (timeline)? What is it like morphologically?

Ionizing radiation injury to the lung can complicate
therapeutic irradiation of the lungs, mediastinum, esophagus,
and breast. Acute radiation pneumonitis occurs 1-6 months
after radiation therapy in 10%-20% of patients receiving therapeutic
irradiation involving the lung fields. The pneumonitis
in these patients is characterized clinically by fever, dyspnea,
and infiltrates on chest x-rays corresponding to the site of previous
irradiation. Morphologically, lungs show diffuse alveolar
damage (Chap. 23), often with severe atypia of hyperplastic
type II alveolar epithelial cells. Some patients with acute
radiation pneumonitis will, after about 6 months, progress to chronic radiation pneumonitis that is characterized by interstitial
fibrosis in the previously irradiated areas (Fig. 26.10).


What are the goals of a successful lung transplant and what must be done to accomplish them? What kinds of infections can occur? What is acute rejection like? What is chronic rejection like?

With lung transplantation, maintaining graft survival and
function involves balancing the two major complications of
transplantation: infection and rejection. Powerful immune
suppression reduces the incidence of rejection while raising
the incidence of infection. Decreased immunosuppression
reduces the incidence of infection while raising the incidence
of rejection. Lung transplant patients are at risk for bacterial,
viral (especially CMV), and fungal infections (including candidiasis,
aspergillosis, and Pneumocystis jiroveci pneumonia;
Chap. 34). Acute rejection typically occurs within 3 months of
transplantation and is characterized by fever, dyspnea, cough,
and chest radiograph infiltrate. Since the symptoms and signs
of acute rejection mimic those of infection, lung biopsy may
be required to establish the diagnosis. The histologic hallmark
of acute rejection in the pulmonary allograft is a perivascular
lymphocytic inflammatory infiltrate [Fig. 26.11 (a)]. Chronic
rejection can present 6-12 months after transplantation and is
present in more than one-half of lung transplant recipients within
5 years of transplantation. The histologic hallmark of chronic
rejection is bronchiolitis obliterans, in which bronchiolar
lumina are obstructed by an inflammatory fibrous exudate
[Fig. 26.11 (b)]. Long-standing chronic rejection can result in
bronchiectasis (Chap. 20).


What is a pleural effusion? When do inflammatory pleural effusions usually occur and what are some possible causes? What is empyema? What are some possible causes? What is its pathophysiology? What is hemorrhagic pleuritis? What are some underlying conditions? In what setting does hydrothorax occur? What is hemothorax? What is chylothorax and when and where does it occur?

A pleural effusion is excess fluid in the pleural space and can
be inflammatory or non-inflammatory (Chap. 19). Inflammatory
pleural effusions typically occur in the setting of pleuritis, which can be due to infection of the lung (Chap. 34), collagen
vascular disorders, uremia, systemic infection, or metastatic
cancer. Empyema is a purulent pleural effusion and can be due
to spread of an intrapulmonary infection to the pleural space or
from lymphohematogenous spread of infection. Typically,
empyema undergoes organization, with the development of
fibrous adhesions that obliterate the pleural space. In hemorrhagic
pleuritis, pleural effusion is sanguineous; underlying
conditions include hemorrhagic diathesis, rickettsial disease,
and neoplastic involvement of the pleural space. Other pleural effusions include hydrothorax (typically in the setting of congestive heart failure), hemothorax (blood in pleural space),
and chylothorax (lymph fluid in pleural space; typically leftsided
and due to thoracic duct trauma or obstruction).


What is a pneumothorax and when does it occur? What is a tension pneumothorax?

Pneumothorax describes air in the pleural space and can
be secondary to trauma, interstitial emphysema (Chap. 20),
asthma (Chap. 21), tuberculosis (Chap. 36), or a lung abscess
(Chap. 34) communicating with the pleural space. Tension
pneumothorax, a medical emergency, is a pneumothorax
wherein the defect acts as a valve, such that air enters the
pleural cavity on inspiration but is prevented from leaving the
pleural cavity on expiration.