Twenty Two Flashcards
What are restrictive lung diseases and what are some common themes among them?
Restrictive lung diseases are characterized by reduced lung
compliance that requires greater pressure to infl ate the lungs
and, clinically, typically are manifest as dyspnea.
Many such
diseases show thickening of alveolar septa and alveolar epithelial
and endothelial injury that lead to
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Q mismatch. With
progression of many such diseases, patients develop severe
hypoxemia and respiratory failure. These are often complicated
with pulmonary hypertension and cor pulmonale
(right ventricular dilatation due to lung disease).
How is ARDS characterized? What about ALI? What is the morphological counterpart of these diseases?
The acute respiratory distress syndrome (ARDS) is a clinical
syndrome characterized by the acute onset of respiratory
distress with hypoxemia, reduced lung compliance, and diffuse
pulmonary infi ltrates in the absence of primary left heart
failure; a less severe form of the syndrome is acute lung
injury (ALI) (Chap. 28). Diffuse alveolar damage (DAD)
is the morphologic counterpart of ALI/ARDS.
What is the pathogenesis of DAD?
The pathogenesis of DAD begins with endothelial damage
or, less frequently, epithelial damage. Within 30 minutes, macrophages
secrete canonical proinfl ammatory cytokines including
TNF-α, IL-1, and IL-8, leading to neutrophil chemotaxis and
activation (Chap. 10). Activated neutrophils secrete oxidants,
proteases, platelet activating factor (PAF), and leukotrienes,
the results of which are tissue damage, edema, inactivation of
pulmonary surfactant, and the formation of hyaline membranes, the morphologic hallmark of DAD (see below). Later, macrophage
secretion of transforming growth factor-beta (TGF-β)
and platelet-derived growth factor (PDGF) causes proliferation
of fi broblasts with subsequent synthesis of collagen. The pathogenesis
of DAD is further discussed in Chap. 28.
What is DAD in the lungs like grossly? Describe the 3 phases of DAD microscopically? What do hyaline membranes consist of?
Morphologically, lungs with DAD show reduced crepitus
and resemble liver in consistency. Early in the course, the
lungs are dense and dark red; as collagen deposition occurs,
their color changes to gray (Fig. 23.1). Microscopically, DAD
shows a spectrum of changes that can be organized into three
phases (Fig. 23.2). The earliest of these is the exudative phase,
with vascular congestion, interstitial and intra-alveolar edema,
alveolar epithelial necrosis, neutrophil margination, dilatation
and/or collapse of alveolar ducts, fi brin thrombi, and hyaline
membranes. Hyaline membranes, the hallmark of DAD, are
composed of edema fl uid and necrotic epithelial cells. Subsequent
to this exudative period is the proliferative phase,
in which there is type 2 pneumocyte hyperplasia as well as
fi broblast infi ltration of the interstitium and the intra-alveolar
exudate (ie, the hyaline membranes). Finally, as fi broblasts
synthesize collagen, DAD enters the fi brotic phase, with
fi brosis of the exudate (also described as organization) and
expansion of the interstitium by fi brosis.
What is the clinical progression of ARDS like? When and how can it be seen clinically?
Clinically, ARDS begins with dyspnea and tachypnea;
early in its course, a chest radiograph may be normal. Subsequently,
the patient develops cyanosis, hypoxemia, and respiratory
failure, at which point a chest radiograph typically shows
diffuse bilateral infi ltrates. As hypoxemia becomes unresponsive
to oxygen therapy, respiratory acidosis often develops. Of
note, oxygen therapy can worsen the alveolar epithelial damage.
ARDS can be complicated by secondary infection of the
hyaline membranes and/or by death, the latter occurring inapproximately 40% of cases in the United States.
What is acute interstitial pneumonia? What is another name for it? What is it like morphologically? What is its mortality rate?
Acute interstitial pneumonia is a rapidly progressive
acute restrictive lung disease with a presentation similar to ARDS
but without a known underlying etiology; an alternate name is
idiopathic ALI-DAD. Morphologically, it closely resembles DAD
and may be indistinguishable from DAD. Mortality rates in various studies have ranged from 33% to 74%. Survivors often
experience complete or near complete recovery.
What is another name for chronic restrictive lung diseases? Why? What do they share in common clinically? Pathogenetically? Morphologically? End stage?
The chronic restrictive lung diseases are also called diffuse
interstitial lung diseases, because changes in the interstitium
dominate the morphologic appearance, and diffuse infi ltrative
diseases, because chest radiographs show diffuse infi ltrates.
Chronic restrictive lung diseases are a heterogeneous group
of disorders without uniform classifi cation, without uniform
terminology, and often without known etiology or pathogenesis.
Nevertheless, they share many clinical and morphological
features and, at end-stage, they may be indistinguishable from
each other. Clinically, patients with chronic restrictive lung
diseases have dyspnea, tachypnea, end-inspiratory crackles,
and eventual cyanosis (Chap. 24). Later, these patients often
develop secondary pulmonary hypertension (Chap. 26) and
right heart failure with cor pulmonale. Pathogenetically, many
of the chronic restrictive lung diseases begin with alveolitis,
leading to distortion of alveolar structure and release of mediators
that incite cell injury and induce fi brosis. Morphologically,
many of the chronic restrictive lung diseases, particularly in
later stages, are characterized by interstitial fi brosis. The endstage
of many of the chronic restrictive lung diseases is the
classic honeycomb lung.
What is idiopathic pulmonary fibrosis and how is it characterized? Pathogenesis? What is it like grossly? Microscopically? Clinically? Treatment?
Idiopathic pulmonary fi brosis (IPF) is a poorly understood,
idiopathic, nongranulomatous chronic restrictive lung
disease that morphologically is characterized by diffuse
interstitial fi brosis. Although many alternate names for the
disease exist, cryptogenic fi brosing alveolitis is the one
most frequently encountered. The pathogenesis of IPF is
poorly understood but appears to involve repeated cycles of
alveolitis (due to an unidentifi ed agent) that are followed by
wound healing with fi broblast proliferation. Grossly, lungs
with well-developed IPF have a pleural surface with a cobblestone
appearance due to wound contraction in interlobular
septa. The cut surface of IPF lungs shows rubbery-to-fi rm,
white patches in subpleural regions and in the interlobular
septa (Fig. 23.3).
Histologically, the morphology of IPF is described as
usual interstitial pneumonia (UIP) (Fig. 23.4). Although
required for a diagnosis of IPF, UIP is not specifi c and can be
seen in other diseases (eg, collagen vascular diseases, asbestosis;
see below). UIP is characterized by regional and temporal
heterogeneity where different lung foci show different
stages of disease. In addition to interstitial fi brosis, magnifi ed
in subpleural zones and interlobular septa, UIP includes characteristic fi broblastic foci and typically shows prominent
type 2 pneumocyte hyperplasia. End-stage UIP shows dilatated
airspaces lined by cuboidal or low columnar epithelium separated
by infl amed fi brous tissue. Patients with IPF typically
present in the fi fth to eighth decade with increasing dyspnea
on exertion and dry cough, followed by hypoxemia, cyanosis,
and digital clubbing. Progression of IPF is unpredictable, but
the mean survival time is approximately three years. The only
defi nitive therapy for IPF is lung transplantation.
What is non specific interstitial pneumonia? What is it like histologically?
Nonspecifi c interstitial pneumonia (NSIP) is an idiopathic,
nongranulomatous lung disease without the defi ning
diagnostic features of better-characterized diseases. Histologically,
NSIP can show a cellular pattern with mild to moderate
expansion of the interstitium by lymphocytes and plasma cells
with either a uniform or patchy distribution [Fig. 23.6(a)].
Alternatively, a fi brosing pattern with diffuse or patchy interstitial
fi brosis is noted [Fig. 23.6(b)]. In contrast to UIP, the
fi brosing pattern of NSIP does typically not show fi broblastic
foci or the regional/temporal heterogeneity of disease.
What is sarcoidosis and how is it characterized? How is the diagnosis made? What is its pathology? What is its epidemiology? What is its etiology? What is its pathogenesis? Genetics? Morphology?
Sarcoidosis is an idiopathic multisystem disease characterized
by granulomatous infl ammation (typically noncaseating)
in many tissues and organs. Since there are many causes
of granulomatous infl ammation—including foreign body, mycobacterial infection, and fungal infection—sarcoidosis is
a diagnosis of exclusion. Though its presentation can include
involvement of virtually any organ, patients typically have
bilateral hilar lymphadenopathy and/or lung involvement.
Sarcoidosis shows a racial bias (black:white of about 10:1)
and a female gender bias. Though the etiology of sarcoidosis
is unknown, its pathogenesis likely involves a type IV hypersensitivity
reaction (cell-mediated, delayed) to a currently
unknown antigen. Familial and racial clustering and association
with certain HLA subtypes imply that development of sarcoidosis may require a genetic predisposition. Many features
of sarcoidosis suggest that it is an infectious disease,
but there is no unequivocal evidence that sarcoidosis has
an infectious etiology. The morphology of sarcoidosis is
nonspecific: noncaseating granulomatous inflammation
(Fig. 23.7).
What is a granuloma? What are the granulomata like in sarcoidosis?
A granuloma is a circumscribed collection of
epithelioid histiocytes [Fig. 23.7(c)]; the term “epithelioid”
is used to describe cells that have more cytoplasm than typical
histiocytes, imparting a resemblance to squamous epithelial
cells. Epithelioid histiocytes can merge with each other, producing a multinucleated giant cell. While multinucleated giant cells
are common in granulomata, not all granulomata contain
them. In sarcoidosis, the granulomata often contain Schaumann
bodies [laminated concretions of calcium and protein,
Fig. 23.7(d)] and asteroid bodies [stellate inclusions within
giant cells, Fig. 23.7(e)]. However, neither Schaumann bodies
nor asteroid bodies are specifi c for sarcoidosis.
What organs do the granulomata of sarcoidosis often involve? What is it like clinically? How does it normally present? What is the prognosis?
As mentioned above, the granulomata in sarcoidosis can
involve virtually any organ but typically involve the pulmonary
interstitium and hilar lymph nodes. Pulmonary involvement is
often complicated by interstitial fi brosis. Other organs that are
commonly involved include skin, eyes, lacrimal glands, salivary
glands, spleen, liver, and skeletal muscle. Clinically, sarcoidosis
is often asymptomatic. If symptomatic, sarcoidosis
ranges from progressive chronicity to periods of activity separated
by periods of remission. Presentation is typically due to respiratory involvement, with dyspnea, cough, chest pain, and
hemoptysis; alternatively, constitutional signs and symptoms
(fever, fatigue, weight loss, anorexia, night sweats) may dominate
the clinical scenario. Specifi c symptoms at presentation
are markedly variable due to the complex of sites showing
involvement. Approximately 65%-70% of patients recover
spontaneously or with steroid therapy and have minimal or
no residual disease, ~20% of patients develop permanent lung
dysfunction or visual impairment, and 10%-15% develop progressive
pulmonary fi brosis with subsequent cor pulmonale or
central nervous system damage.
What is hypersensitivity pneumonitis? How does it begin? What is the acute phase like both clinically and histologically? What is the chronic phase like clinically and histologically? What kind of hypersensitivity reactions are involved in the acute and chronic?
Hypersensitivity pneumonitis is typically an occupational
disease that begins with alveolar damage from exposure
to an organic antigen. The acute phase of the disease occurs
4-6 hours after antigen exposure in a previously sensitized host,
likely represents a type III hypersensitivity reaction (immune complex), and is typifi ed by diffuse and nodular infi ltrates on
chest radiograph, restrictive pattern of pulmonary function
tests, and neutrophilic infl ammation. With continuous antigen
exposure, the disease enters its chronic phase with respiratory
failure, dyspnea, cyanosis, decreased lung compliance, and
decreased total lung capacity. The chronic phase is a type IV
hypersensitivity reaction (delayed, cell-mediated) characterized
histologically by lymphocytes, plasma cells, and foamy
histiocytes in alveoli, alveolar walls, and around terminal
bronchioles; interstitial fi brosis; obliterative bronchiolitis;
and, in about two-thirds of cases, granulomata. Of note, the
eosinophilia that is typical of type I hypersensitivity reactions
is not a signifi cant feature of hypersensitivity pneumonitis. If
the offending antigen is removed during the acute phase, the
disease resolves in weeks. Once the disease has progressed to
its chronic phase, resolution can be slow, and approximately
5% of patients develop respiratory failure and die. Table 23.2
summarizes the myriad diseases that represent forms of hypersensitivity
pneumonitis.
What is pulmonary eosinophilia? What is the clinical scenario? What is it like morphologically? How are acute eosinohilic pneumonia, simply pulmonary eosinophilia, tropical eosinophilia, secondary chronic pulmonary eosinophilia, and idiopathic chronic eosinophilic pneumonia characterized by?
Pulmonary eosinophilia is a collection of diseases with
similar morphologies of eosinophilic infi ltration of the pulmonary
interstitium and/or alveolar spaces (Fig. 23.9) and similar
clinical scenarios of corticosteroid-responsive fever, night sweats,
and dyspnea. Acute eosinophilic pneumonia with respiratory
failure is an idiopathic illness with rapid onset of fever, dyspnea,
and potentially fatal hypoxemic respiratory failure. Simple pulmonary
eosinophilia (Löffl er syndrome) is characterized by
transient pulmonary eosinophilic infi ltrates and peripheral blood
eosinophilia. Tropical eosinophilia represents a microfi larial
infection. Secondary chronic pulmonary eosinophilia occurs
in a number of settings, including certain infections (parasitic,
fungal, bacterial), drug allergies, asthma, allergic bronchopulmonary
aspergillosis (Chap. 20), and polyarteritis nodosa. Idiopathic
chronic eosinophilic pneumonia is characterized by
interstitial and intra-alveolar lymphocytic and eosinophilic infi ltrates
in peripheral lung fi elds. From the morphologic perspective,
many of these diseases are indistinguishable, thus giving
rise to the morphologic term pulmonary eosinophilia.
What are some smoking related chronic restrictive lung diseases? Describe them morphologically and clinically.
Though smoking-related lung disease is frequently
obstructive (see Chap. 20 for discussions of emphysema and
chronic bronchitis), there are several smoking-related restrictive
lung diseases. Desquamative interstitial pneumonitis
(DIP) and respiratory bronchiolitis-associated interstitial
lung disease are thought of as opposite ends of a spectrum
of interstitial lung disease that may develop in smokers; the
pathogenesis of both is unknown. In DIP [Fig 23.10(a), (b)],
there is mononuclear interstitial infl ammation, an abundance
of airspace macrophages with dusty brown cytoplasmic
pigment, and type 2 pneumocyte hyperplasia. The airspace macrophages in DIP typically clump together, resulting in an
appearance that was historically (and erroneously) interpreted
as desquamated alveolar epithelium. In respiratory bronchiolitis-
associated interstitial lung disease, there is patchy
bronchiolocentric distribution of pigmented macrophages
[Fig. 23.10(c)], and there can be histologic overlap with DIP.
Both DIP and respiratory bronchiolitis-associated interstitial
lung disease present in the fourth to fi fth decade, show a male
gender bias (male:female ratio of about 2:1), may occur with
insidious onset of dyspnea and cough, and improve with cessation
of smoking and steroid therapy.
