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2H Sytem Patho: LUNGS > Chapter 15: Lung: Chronic Diffuse Interstitial (Restrictive) Diseases > Flashcards

Chapter 15: Lung: Chronic Diffuse Interstitial (Restrictive) Diseases Flashcards

1
Q

What is Chronic interstitial disease?

A

Chronic interstitial diseases are a heterogeneous group of disorders characterized
predominantly by inflammation and fibrosis of the pulmonary connective tissue, principally the
most peripheral and delicate interstitiumin thealveolar walls.

Many of the entities are of
unknown cause and pathogenesis,some have anintra-alveolar as well as an interstitial
component,and there isfrequent overlap in histologic features among the different conditions.
These disorders account for about 15% of noninfectious diseases seen by pulmonary
physicians.

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2
Q

In general, the clinical and pulmonary functional changes of Chronic Diffuse Interstitial (Restrictive) Diseases are:

A

those of restrictive lung disease
(see the earlier discussion of obstructive versus restrictive pulmonary diseases).

Patients have
dyspnea, tachypnea, end-inspiratory crackles, and eventual cyanosis, without wheezing or
other evidence of airway obstruction.

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3
Q

What is the classic Chronic Diffuse Interstitial (Restrictive) Diseases?

A

The classic physiologic features are reductions in carbon
monoxide diffusing capacity, lung volume, and compliance.

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4
Q

Why is Chronic Diffuse Interstitial (Restrictive) Diseases called infiltritative?

A

Chest radiographs show bilateral
infiltrative lesions in the form of small nodules, irregular lines,orground-glass shadows, hence
the term infiltrative.

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5
Q

What are the circumstances in patients with Chronic infitritative ( restrictive) disease?

A

Eventually, secondary pulmonary hypertension and right-sided heart failure
with cor pulmonale may result.

Although the entities can often be distinguished in the early
stages.

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6
Q

Why is hard to differentitate the advanced forms of Chronic Infiltrative ( Restrictive) Disease?

A

the advanced forms are hard to differentiate because they result in scarring and gross
destruction of the lung, often referred to as end-stage lung or honeycomb lung

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7
Q

How do you categorized Chronic infiltrative ( restrictive) disease?

A

Diffuse
restrictive diseases are categorized based on histology and clinical features

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8
Q

TABLE 15-5 – Major Categories of Chronic Interstitial Lung Disease

A
  • FIBROSING
  • GRANULOMATOUS
  • EOSINOPHILIC
  • SMOKING RELATED
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9
Q

TABLE 15-5 – Major Categories of Chronic Interstitial Lung Disease

FIBROSING

A
  • Usual interstitial pneumonia (idiopathic pulmonary fibrosis)
  • Nonspecific interstitial pneumonia
  • Cryptogenic organizing pneumonia
  • Associated with connective tissue diseases
  • Pneumoconiosis
  • Drug reactions
  • Radiation pneumonitis
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10
Q

TABLE 15-5 – Major Categories of Chronic Interstitial Lung Disease

GRANULOMATOUS

A
  • Sarcoidosis
  • Hypersensitivity pneumonitis
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11
Q

TABLE 15-5 – Major Categories of Chronic Interstitial Lung Disease

SMOKING RELATED

A
  • Desquamative interstitial pneumonia
  • Respiratory bronchiolitis-associated interstitial lung disease
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12
Q

What is Idiopathic Pulmonary Fibrosis?

A

The term idiopathic pulmonary fibrosis (IPF) refers to a clinicopathologic syndrome with
characteristic radiologic, pathologic, and clinical features.

**In Europe the term cryptogenic
fibrosing alveolitis is more popular

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13
Q

What is the other name of Idiopathic Pulmonary Fibrosis ?

A

cryptogenic fibrosing alveolitis

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14
Q

The histologic pattern of fibrosis is referred to as __________, which is required for the diagnosis of IPF but can also be seen in
other diseases,notably connective tissue diseases, chronic hypersensitivity pneumonia, and
asbestosis.

A 
usual
interstitial pneumonia (UIP)
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15
Q

The International Multidisciplinary Consensus Classification is an excellent
reference for definitions and understanding of idiopathic interstitial pneumonias

A
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16
Q

What is the pathogenesis of IPF?

A

The earlier view was that IPF is initiated by an
unidentified insultthatgives rise to chronic inflammation resulting in fibrosis.

The dismal failure
of potent anti-inflammatory therapy in altering the course of the disease did not support this
view.

The current concept is that IPF is caused by “repeated cycles” of epithelial
activation/injury by some unidentified agent.

There is inflammation and induction of TH2 type T
cell response characterized by the presence of eosinophils, mast cells, IL-4 and IL-13 in the
lesions.

But the significance of this inflammatory response is unknown.

Abnormal epithelial
repair at these sites gives rise to exuberant fibroblastic/myofibroblastic proliferation, leading to
the “fibroblastic foci” that are so characteristic of IPF ( Fig. 15-13 ).

The circuits that drive such
aberrant epithelial repair are not fully understood, but all evidence points to TGF-β1 as the
driver of the process.

TGF-β1 is known to be fibrogenic and is released from injured type I
alveolar epithelial cells ( Fig. 15-13 ).

It favors the transformation of fibroblasts into
myofibroblasts and deposition of collagen and other extracellular matrix molecules.

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17
Q

What are fibroblastic foci that are so characteristic of IPF?

A

Abnormal epithelial
repairat these sites gives rise toexuberant fibroblastic/myofibroblastic proliferation, leading to
the “fibroblastic foci” that are so characteristic of IPF ( Fig. 15-13 ).

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18
Q

In IPF, though the aberrant epithelial repair isnt fully understood, where does all the evidence of pathology point to?

A

The circuits that drive such
aberrant epithelial repair are not fully understood, but all evidence points to TGF-β1 as the
driver of the process.

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19
Q

What is TGF- B1?

A

TGF-β1 is known to be fibrogenic and is released from injured type I alveolar epithelial cells ( Fig. 15-13 ).

  • *It favors the transformation of fibroblasts** into
  • *myofibroblasts and deposition of collagen** and other extracellular matrix molecules.
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20
Q
A

FIGURE 15-13 Schematic representation of current understanding of the pathogenesis of
idiopathic pulmonary fibrosis.

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21
Q

What are the two molecules regulated by TGF-β1?

A
  • telomerase activity
  • caveolin-1
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22
Q

What is the relation of telomerase shortening in IPF?

A

The concept that there is an intrinsic abnormality of tissue repair in IPF is supported by the
finding that some patients with familial pulmonary fibrosis have mutations that shorten
telomeres.

Recall that telomeres control cell replications (see Chapters 1 and 7 and with

  • *shortening of telomeres alveolar epithelial cells undergo rapid senescence and
    apoptosis. **[56,] [57]

Interestingly, TGF-β1 negatively regulates telomerase activity , thus
facilitating epithelial cell apoptosis and the cycle of death and repair.

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23
Q

What does caveolin- 1 does?

A

Another molecule
regulated by TGF-β1 is caveolin-1, the predominant structural protein of caveolae, flaskshaped
invaginations of the plasma membrane present in many terminally differentiated cells.

Caveolin-1 acts as an endogenous inhibitor of pulmonary fibrosis by limiting TGF-β1–induced
production of extracellular matrix and restoring alveolar epithelial repair processes.

Caveolin-1
is decreased in epithelial cells and fibroblasts of IPF patients, and overexpression of caveolin-1
in a mouse model limits fibrosis. [59]

Such down-regulation may be mediated by the ability of TGF-β1 to attenuate the expression of caveolin-1 in fibroblasts.

Thus, it seems that TGF-β1
has its fingerprints on multiple pathways that regulate pulmonary fibrosis.

Therapeutics directed
toward neutralizing TGF-β1, enhancing telomerase activity or delaying telomere shortening, or
augmenting caveolin-1 may lead to novel treatments for IPF in the future.

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24
Q

What is the macroscopic appearance of IPF?

A

Grossly, the pleural surfaces of the lung are cobblestoned as a result of the
retraction of scars along the interlobular septa.

The cut surface shows fibrosis (firm, rubbery
white areas)of thelung parenchyma with lower-lobe predominanceanda distinctive
distribution in the subpleural regions and along the interlobular septa.

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25
Q

In IPF the predominance of fibrosis is on the______ and with a distinctive distribution where?

A

The cut surface shows fibrosis (firm, rubbery
white areas) of the lung parenchyma with lower-lobe predominance and a distinctive
distribution in the subpleural regions and along the interlobular septa.

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26
Q

What is the microscopic appearance of IPF?

A

Microscopically,
the hallmark of UIP is patchy interstitial fibrosis, which varies in intensity ( Fig. 15-14 ) and
age.

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27
Q

What is the contents of the earliest lesion in IPF?

A

The earliest lesions contain exuberant fibroblastic proliferation (fibroblastic foci).

With
time these areas become more collagenous and less cellular.

Quite typical is the coexistence
of both early and late lesions ( Fig. 15-15 ).

The dense fibrosis causes the destruction of
alveolar architecture and formation of cystic spaces lined by hyperplastic type II pneumocytes
or bronchiolar epithelium (honeycomb fibrosis)

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28
Q

With adequate sampling, these diagnostic
histologic changes(i.e.,areas of dense collagenous fibrosis with relatively normal lung and
fibroblastic foci)can be identified even in advanced IPF.

T or F

A

True

There is mild to moderate
inflammation within the fibrotic areas, consisting of mostly lymphocytes, and a few plasma
cells, neutrophils, eosinophils, and mast cells.

Foci of squamous metaplasia and smooth
muscle hyperplasia may be present.

Pulmonary arterial hypertensive changes (intimal fibrosis and medial thickening) are often present. In acute exacerbations diffuse alveolar damage is
superimposed on the UIP pattern

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29
Q
A

FIGURE 15-14 Usual interstitial pneumonia. The fibrosis is more pronounced in the
subpleural region.

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30
Q
A

FIGURE 15-15 Usual interstitial pneumonia.

Fibroblastic focus with fibers running parallel
to surface and bluish myxoid extracellular matrix. Honeycombing is present on the left.

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31
Q

What is the clinical course of IPF?

A

IPF begins insidiously, with gradually increasing dyspnea on exertion and dry cough.

Most
patients are 40 to 70 years old at the time of presentation.

Hypoxemia, cyanosis, and clubbing
occur late in the course.

The progression in an individual patient is unpredictable.

Most patients
have a gradual deterioration of their pulmonary status, despite medical treatment (steroids,
cyclophosphamide, or azathioprine).

In some IPF patients, there are acute exacerbations of the
underlying diseasewith arapid downhill clinical course.

The mean survival is 3 years or less.
Lung transplantation is the only definitive therapy currently available.

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32
Q

What is the only definitive treatment for IPF?

A

Lung transplantation is the only definitive therapy currently available.

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33
Q

What is Nonspecific Interstitial Pneumonia?

A

The concept of nonspecific interstitial pneumonia (NSIP) emerged when it was realized that
there is a group of patients with diffuse interstitial lung disease of unknown etiology whose lung
biopsies fail to show diagnostic features of any of the other well-characterized interstitial
diseases.

Despite its “nonspecific” name, NSIP has distinct radiologic and histologic features
and is important to recognize, since these patients have a much better prognosis than do those
with UIP

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34
Q

Which has a better prognosis. IUP or NSIP?

A

Despite its “nonspecific” name, NSIP has distinct radiologic and histologic features
and is important to recognize, since these patients have a much better prognosis than do those
with UIP.

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35
Q

Morphology.

On the basis of its histology,

NSIP is divided into ____________.

A
  • cellular and
  • fibrosing patterns
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36
Q

What is the cellular pattern of the NSIP?

A

The cellular pattern consists primarily of mild to moderate chronic interstitial inflammation, containing lymphocytes and a few plasma cells, in a uniform or patchy
distribution.

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37
Q

What is the fibrosing pattern of the NSIP?

A

What is the cellular pattern of the NSIP?

The fibrosing pattern consists of diffuse or patchy interstitial fibrosis without the
temporal heterogeneity that is characteristic of UIP.

  • **Fibroblastic foci and honeycombing are
    absent. ***

However, in some patients both NSIP and UIP patterns can be seen in different areas
of the lung; the prognosis in these is the same as for UIP

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38
Q

Fibroblastic foci and honeycombing are
present in NSIP?

t or F

A

False

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39
Q

What is the Clinical Course NSIP?

A

Patients present with dyspnea and cough of several months’ duration.

They are typically
between 46 and 55 years of age.

Those having the NSIP cellular pattern are somewhat younger than those with the fibrosing pattern or UIP.

Patients with the cellular pattern have a better
outcomethan do those with fibrosing pattern and UIP

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40
Q

What is Cryptogenic Organizing Pneumonia?

A

Cryptogenic organizing pneumonia is synonymous with the popular term bronchiolitis obliterans
organizing pneumonia;however, theformer is now preferred,since it conveys the essential
features of a clinicopathologic syndromeof unknownetiology and avoids confusion with airway
diseases such as bronchiolitis obliterans.

Patients present with cough and dyspnea and have
subpleural or peribronchial patchy areas of airspace consolidation radiographically

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41
Q

What is the histologic appearance of cryptogenic organizing pneumonia?

A

Histologically, cryptogenic organizing pneumonia is characterized by the presence of polypoid
plugs of loose organizing connective tissue (Masson bodies)within alveolar ducts, alveoli ( Fig.
15-16 ), and often bronchioles.

The connective tissue is all of the same age, and the underlying lung architecture is normal.

There is no interstitial fibrosis or honeycomb lung.

Some patients
recover spontaneously, but most need treatment with oral steroids for 6 months or longer for
complete recovery.

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42
Q

What are Masson Bodies?

A

presence of polypoid plugs of loose organizing connective tissue (Masson bodies)

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43
Q
A

FIGURE 15-16 Cryptogenic organizing pneumonia. Some alveolar spaces are filled with
balls of fibroblasts (Masson bodies), while the alveolar walls are relatively normal. A, Low
power; B, high power

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44
Q

It is important to recognize that organizing pneumonia with intra-alveolar fibrosis is also often
seen as a response to infections or inflammatory injury of the lungs. [66]

These include viral
and bacterial pneumonia, inhaled toxins, drugs, connective tissue disease, and graft-versushost
disease in bone marrow transplant recipients.

The prognosis for these patients is the same
as that for the underlying disorder.

A
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45
Q

What is Pulmonary Involvement in Connective Tissue Diseases?

A

Many connective tissue diseases, notably systemic lupus erythematosus, rheumatoid arthritis,
progressive systemic sclerosis (scleroderma), dermatomyositis-polymyositis, and mixed
connective tissue disease, can involve the lung to a lesser or greater degree at some time in
their course.

Pulmonary involvement can occur in different patterns; NSIP, UIP (similar to that
seen in IPF), vascular sclerosis, organizing pneumonia, and bronchiolitis are the most common.

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46
Q

Many connective tissue diseases, notably_______________, can involve the lung to a lesser or greater degree at some time in
their course.

A
  • systemic lupus erythematosus,
  • rheumatoid arthritis,
  • progressive systemic sclerosis (scleroderma),
  • dermatomyositis-polymyositis, and
  • mixed connective tissue disease
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47
Q

In the pulmonary involvement in Connective tissue diseases, what are the patterns?

A

Pulmonary involvement can occur in different patterns;

  • NSIP, UIP (similar to that seen in IPF),
  • vascular sclerosis,
  • organizing pneumonia,
  • and bronchiolitis

​ are the most common

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48
Q

Rheumatoid arthritis: pulmonary involvement may occur in 30% to 40% of patients as

A
  • (1) chronic pleuritis, with or without effusion;
  • (2) diffuse interstitial pneumonitis and fibrosis;
  • (3) intrapulmonary rheumatoid nodules; or
  • (4) pulmonary hypertension
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49
Q

What is the more common pattern in Systemic sclerosis?

A

• Systemic sclerosis (scleroderma): diffuse interstitial fibrosis (NSIP pattern more common
than UIP)

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50
Q

What is the more common pattern in Lupus erythematosus?

A

• Lupus erythematosus: patchy, transient parenchymal infiltrates, and occasionally severe
lupus pneumonitis

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51
Q

Pulmonary involvement in these diseases is usually associated with a variable prognosis, partly
dependent on the type of pulmonary disease, although it is still better than that of idiopathic
UIP

A
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52
Q

What is pneumoconiosis?

A

The term pneumoconiosis was originally coined to describe the non-neoplastic lung reaction to
inhalation of mineral dusts encountered in the workplace.

Now it also includes diseases induced
by organic as well as inorganic particulatesandchemical fumes and vapors.

A simplified
classification is presented in Table 15-6 . Regulations limiting worker exposure have resulted in
a marked decrease in dust-associated diseases.

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53
Q

TABLE 15-6 – Lung Diseases Caused by Air Pollutants

A
  • MINERAL DUSTS
  • ORGANIC DUSTS THAT INDUCE HYPERSENSITIVITY PNEUMONITIS
  • ORGANIC DUSTS THAT INDUCE ASTHMA
  • CHEMICAL FUMES AND VAPORS
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54
Q

TABLE 15-6 – Lung Diseases Caused by Air Pollutants

MINERAL DUSTS

A
  • Coal dust
  • Silica
  • Asbestos
  • Beryllium
  • Iron oxide
  • Barium sulfate
  • Tin oxide
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55
Q

TABLE 15-6 – Lung Diseases Caused by Air Pollutants

ORGANIC DUSTS THAT INDUCE HYPERSENSITIVITY PNEUMONITIS

A
  • Moldy hay
  • Bagasse
  • Bird droppings
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56
Q

TABLE 15-6 – Lung Diseases Caused by Air Pollutants

ORGANIC DUSTS THAT INDUCE ASTHMA

A
  • Cotton, flax, hemp
  • Red cedar dust
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57
Q

TABLE 15-6 – Lung Diseases Caused by Air Pollutants

CHEMICAL FUMES AND VAPORS

A
  • Nitrous oxide,
  • sulfur dioxide,
  • ammonia,
  • benzene,
  • insecticides
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58
Q

What are the diseases caused by Coal dust?

A
  • Anthracosis Coal mining (particularly hard coal)
  • Macules
  • Progressive massive fibrosis
  • Caplan syndrome
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59
Q

What are the diseases caused by Silica ?

A
  • Silicosis
  • Caplan syndrome
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60
Q

What are the diseases caused by Asbestos ?

A
  • Asbestosis
  • Pleural plaques
  • Caplan syndrome
  • Mesothelioma
  • Carcinoma of the lung,
    larynx, stomach, colon
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61
Q

What are the Lung Diseases Caused by Beryllium?

A
  • Acute berylliosis
  • Beryllium granulomatosis
  • Lung carcinoma
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62
Q

What are the Lung Diseases Caused byIron oxide?

A

Siderosis

Exposure
Welding

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63
Q

What is the lung disease caused by Barium sulfate?

A

Baritosis

Which is an exposure from mining?

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64
Q

What is the lung disease caused by Tin oxide?

A

Stannosis

Exposure from Mining

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65
Q

What is the lung disease caused by Moldy hay?

A

Farmer’s lung

from farming

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66
Q

What is the lung disease caused by Bagasse?

A

Bagassosis

from Manufacturing wallboard, paper

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67
Q

What is the lung disease caused by Bird droppings?

A

Bird-breeder’s lung

From Bird handling

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68
Q

What is the lung disease caused by Cotton, flax, hemp?

A

Byssinosis

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69
Q

What is the lung disease caused by Red cedar dust?

A
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70
Q

What is the lung disease caused by Nitrous oxide, sulfur dioxide,
ammonia, benzene, insecticides?

A
  • Bronchitis, asthma
  • Pulmonary edema
  • ARDS
  • Mucosal injury
  • Fulminant poisoning

From occupational and accidental exposure

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71
Q

Although the pneumoconioses result from well-defined occupational exposure to specific
airborne agents, particulate air pollution also has deleterious effects on the general population,
especially in urban areas. Studies have found increased morbidity (e.g., asthma incidence) and
mortality rates in populations that are exposed to high ambient air particulate levels, [68,] [69]
leading to calls for greater efforts to reduce the levels of particulates in urban air

A
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72
Q

The development of a pneumoconiosis depends on

A

(1) the amount of dust retained in the lung
and airways;

(2) the size, shape, and therefore buoyancy of the particles;
(3) particle solubility and physiochemical reactivity; and

(4) the possible additional effects of other irritants (e.g.,
concomitant tobacco smoking).

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73
Q

The amount of dust retained in the lungs is determined by :

A

the dust concentration in ambient air,
the duration of exposure, and the effectiveness of clearance mechanisms.

Any influence, such
as cigarette smoking, that affects the integrity of the mucociliary apparatus significantly
predisposes to the accumulation of dust.

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74
Q

The most dangerous particles range from _______- in
diameter because they may reach the terminal small airways and air sacs and settle in their
linings.

A

1 to 5 μm

Under normal conditions there is a small pool of intra-alveolar macrophages, and this is
expanded by recruitment of more macrophages when dust reaches the alveolar spaces.

The
protection provided by phagocytosis of particles, however, can be overwhelmed by a large dust
burden by specific chemical interactions of the particles with cells.

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75
Q

The solubility and cytotoxicity of particles , which are influenced to a considerable extent by
their size, modify the nature of the pulmonary response.

In general, the smaller the particle, the
more likely it is to appear in the pulmonary fluids and reach toxic levels rapidly, depending, of
course, on the solubility of the agent.

T or F

A

True

Therefore, smaller particles tend to cause acute lung
injury.

Larger particles resist dissolution and so may persist within the lung parenchyma for
years.

These tend to evoke fibrosing collagenous pneumoconioses, such as is characteristic of
silicosis.

Some of the particles may be taken up by epithelial cells or may cross the epithelial
cell lining and interact directly with fibroblasts and interstitial macrophages.

Some may reach
the lymphatics by direct drainage or within migrating macrophages and thereby initiate an
immune response to components of the particulates or to self-proteins modified by the particles
or both. This response amplifies the intensity and the duration of the local reaction.

Although
tobacco smoking worsens the effects of all inhaled mineral dusts, the effects of asbestos are
particularly magnified by smoking. The effects of inhaled particles are not confined to the lung alone, since solutes from particles can enter the blood and lung inflammation invokes systemic
responses

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76
Q

In general, only a small percentage of exposed people develop occupational respiratory
diseases, implying a genetic predisposition to their development. [71]

In one study, genetic
variation of serum and erythrocytic proteins was shown to correlate with susceptibility to
developing silicosis, chronic bronchitis, and occupational asthma. [72]

Many of the diseases
listed in Table 15-6 are quite uncommon. Hence only a selected few that cause fibrosis of the
lung are presented next.

A
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77
Q

What is Coal Workers’ Pneumoconiosis?

Dust reduction measures in coal mines around the globe have drastically reduced the incidence

of coal workers’ pneumoconiosis (CWP).

The spectrum of lung findings in coal workers is wide,
varying from

A
  • (1) asymptomatic anthracosis to
  • (2) simple CWP with little to no pulmonary dysfunction to
  • (3) complicated CWP, or progressive massive fibrosis (PMF), in which lung function is compromised. [73]
78
Q

What is the pathogenesis of CWP?

A

The pathogenesis of complicated CWP, particularly what causes
the lesions of simple CWP to progress to PMF, is incompletely understood.

Contaminating silica
in the coal dust can favor progressive disease.

In most cases, carbon dust itself is the major
culprit, and studies have shown that complicated lesions contain much more dust than simple
lesions.

79
Q

What is anthracosis?

A

. Anthracosis is the most innocuous coal-induced pulmonary lesion in coal
miners and is also seen to some degree in urban dwellers and tobacco smokers.

Inhaled
carbon pigment is engulfed by alveolar or interstitial macrophages, which then accumulate in
the connective tissue along the lymphatics, including the pleural lymphatics, or in organized
lymphoid tissue along the bronchi or in the lung hilus.

80
Q

Simple CWP is characterized by:

A

Simple CWP is characterized by coal macules (1 to 2 mm in diameter) and the somewhat
larger coal nodules.

The coal macule consists of carbon-laden macrophages; the nodule
also contains small amounts of a delicate network of collagen fibers.

Although these lesions
are scattered throughout the lung, the upper lobes and upper zones of the lower lobes are
more heavily involved.

81
Q

Simple CWP is primiary located where?

A

They are located primarily adjacent to respiratory bronchioles, the
site of initial dust accumulation.

In due course dilation of adjacent alveoli occurs, a condition sometimes referred to as centrilobular emphysema.

82
Q

What is Complicated CWP?

A 
Complicated CWP (progressive massive fibrosis) **occurs on a background of simple CWP**
and **generally requires many years to develop**.

It is characterized by intensely blackened
scars larger than 2 cm,sometimes up to 10 cmingreatest diameter.

They are usually
multiple ( Fig. 15-17 ).
Microscopically the lesions consist of dense collagen and pigment.
The center of the lesion is often necrotic, most likely due to local ischemia.

83
Q
A

FIGURE 15-17 Progressive massive fibrosis superimposed on coal workers’
pneumoconiosis.

The large, blackened scars are located principally in the upper lobe.
Note the extensions of scars into surrounding parenchyma and retraction of adjacent
pleura.

84
Q

CWP is usually a benign disease that causes little decrement in lung function.

T or F

A

True

85
Q

Even mild forms
of complicated CWP fail to demonstrate abnormalities of lung function.

In a minority of cases
(fewer than 10%), PMF develops, leading to increasing pulmonary dysfunction, pulmonary
hypertension, and cor pulmonale.

Once PMF develops, it may become progressive even if further exposure to dust is prevented.

Unlike silicosis (discussed later), there is no convincing
evidence that coal dust increases susceptibility to tuberculosis.

There is some evidence that exposure to coal dust increases the incidence of chronic bronchitis and emphysema, independent of smoking.

Thus far, however, there is no compelling evidence that CWP in the
absence of smoking predisposes to cancer.

A
86
Q

What is Silicosis?

A

Silicosis is a lung disease caused by inhalation of crystalline silicon dioxide (silica). [74]

Currently the most prevalent chronic occupational disease in the world , silicosis usually
presents after decades of exposure as a slowly progressing, nodular, fibrosing pneumoconiosis.

As shown in Table 15-6 , workers in a large number of occupations are at risk, especially
sandblasters and many mine workers

. Less commonly, heavy exposure over months to a few years can result in acute silicosis, a disorder characterized by the accumulation of abundant
lipoproteinaceous material within alveoli (identical morphologically to alveolar proteinosis, which
is discussed later).

87
Q

Currently what is the most prevalent chronic occupational disease in the world?

A

Currently the most prevalent chronic occupational disease in the world , silicosis usually
presents after decades of exposure as a slowly progressing, nodular, fibrosing pneumoconiosis.

88
Q

Silica occurs in both crystalline and amorphous forms, but crystalline forms (including quartz,
crystobalite, and tridymite) are much more fibrogenic.

Of these, what is the most implicated of these in silicosis?

A

Of these, quartz is most commonly
implicated in silicosis.

89
Q

What is the pathophysiology of silicosis?

A

After inhalation, the particles interact with epithelial cells and macrophages.

Within the macrophages silica causes activation and release of mediators .

Such
mediators include IL-1, TNF, fibronectin, lipid mediators, oxygen-derived free radicals, and
fibrogenic cytokines. [75,] [76]

Especially compelling is evidence incriminating TNF, since anti-TNF monoclonal antibodies can block lung collagen accumulation in mice given silica
intratracheally.

It has been noted that when mixed with other minerals, quartz has a reduced
fibrogenic effect.

This phenomenon is of practical importance because quartz in the workplace
is rarely pure.

Thus, miners of the iron-containing ore hematite may have more quartz in their lungs than some quartz-exposed workers and yet have relatively mild lung disease because the
hematite somehow provides a protective effect.

Although amorphous silicates are biologically
less active than crystalline silica, heavy lung burdens of these minerals may also produce
lesions.

90
Q

What is the characteristic of Silicosis in early phase?

A

Silicosis is characterized grossly in its early stages by tiny, barely palpable, discrete pale to blackened (if coal dust is also present) nodules in the upper zones of the
lungs

91
Q

What happens as the Silicosis progress?

A

As the disease progresses, these nodules may coalesce into hard, collagenous
scars ( Fig. 15-18 ).

Some nodules may undergo central softening and cavitation. This
change may be due to superimposed tuberculosis or to ischemia.

Fibrotic lesions may also
occur in the hilar lymph nodes and pleura. Sometimes, thin sheets of calcification occur in the
lymph nodes and are seen radiographically as eggshell calcification (i.e., calcium
surrounding a zone lacking calcification).

92
Q

What is eggshell calcification?

A

In Silicosis, fibrotic lesions may also
occur in the hilar lymph nodes and pleura.

Sometimes, thin sheets of calcification occur in the
lymph nodes and are seen radiographically as eggshell calcification(i.e., calcium
surrounding a zone lacking calcification).

If the disease continues to progress, expansion and
coalescence of lesions may produce progressive massive fibrosis.

93
Q

What is the hitologic apperance in Silicosis?

A

Histologic examination
reveals that the nodular lesions consist of concentric layers of hyalinized collagen surrounded
by a dense capsule of more condensed collagen ( Fig. 15-19 )

. Examination of the nodules by
polarized microscopy reveals the birefringent silica particles

94
Q
A

FIGURE 15-18 Advanced silicosis (transected lung). Scarring has contracted the upper
lobe into a small dark mass (arrow). Note the dense pleural thickening

95
Q
A

FIGURE 15-19 Several coalescent collagenous silicotic nodules.

96
Q

What is the chest xray appearance of SIlicosis?

A

Chest radiographs typically show a fine nodularity in the upper zones of the lung, but pulmonary
functions are either normal or only moderately affected.

Most patients do not develop shortness
of breath until late in the course, after progressive massive fibrosis is present.

97
Q

Silicosis may
be progressive even if the patient is no longer exposed.

T or F

A

True

The disease may
be progressive even if the patient is no longer exposed.

The disease is slow to kill, but impaired
pulmonary function may severely limit activity.

98
Q

What Lung Diseases Caused by Air Pollutants is associated with inc susceptibility to tb?

A
  • Silicosis is associated with an increased*
  • susceptibility to tuberculosis.*

It is postulated that silicosis results in a depression of cellmediatedimmunity, and crystalline silica may inhibit the ability of pulmonary macrophages to kill
phagocytosed mycobacteria.

Nodules of silicotuberculosis often display a central zone of caseation.

The relationship between silica and lung cancer is contentious. In 1997, the
International Agency for Research on Cancer (IARC) concluded that crystalline silica from
occupational sources is carcinogenic in humans. However, this subject continues to be
controversial.

99
Q

Nodules of silicotuberculosis often display a

_________-

A

central zone of caseation.

100
Q

Asbestos is a family of crystalline hydrated silicates that form fibers.

Use of asbestos is
seriously restricted in many developed countries; however, there is little, if any, control in less
developed parts of the world. [77]

On the basis of epidemiologic studies, occupational exposure
to asbestos is linked to

A
  • Localized fibrous plaques or, rarely, diffuse pleural fibrosis
  • Pleural effusions
  • Parenchymal interstitial fibrosis (asbestosis)
  • Lung carcinoma
  • Mesotheliomas
  • Laryngeal and perhaps other extrapulmonary neoplasms, including colon carcinomas
101
Q

An increased incidence of asbestos-related cancer in family members of asbestos workers has
alerted the general public to the potential hazards of asbestos in the environment.

The proper
public health policy toward low-level exposures that might be encountered in old buildings or
schools is unsettled: some experts question the wisdom of expensive asbestos abatement
programs for environments with airborne fiber counts that are as much as 100-fold lower than
allowed by occupational standards

A
102
Q

What dictates whether Asbestos can cause disease?

A

Concentration, size, shape, and solubility of the different forms of asbestos dictate whether it
causes disease

103
Q

There are two distinct geometric forms of asbestos: ________________.

A
  • serpentine and
  • amphibole
104
Q

Serpentine form of Asbestos account for?

A

The serpentine chrysotile chemical form accounts for most of the asbestos used in
industry.

105
Q

What form of Asbestos are more pathogenic than chrysotiles
particularly with respect to induction of malignant pleural tumors (mesotheliomas)?

A

Amphiboles, even though less prevalent, are more pathogenic than chrysotiles
particularly with respect to induction of malignant pleural tumors (mesotheliomas).

***BOARD EXAM Q

106
Q

The greater pathogenicity of amphiboles is apparently related to their _____________.

A

aerodynamic properties
and solubility

107
Q

Why is Chrysotiles are likely to become impacted in the upper respiratory passages and removed by the mucociliary elevator?

A

Chrysotiles, with their more flexible, curled structure, are likely to become
impacted in the upper respiratory passages and removed by the mucociliary elevator.

Furthermore, once trapped in the lungs, chrysotiles are gradually leached from the tissues
because they are more soluble than amphiboles.

108
Q

What is the reason why amphiboles penetrate epithelial cells and reach the interstitium?

A

In contrast, the straight, stiff amphiboles may
align themselves in the airstream and thus be delivered deeper into the lungs, where they can
penetrate epithelial cells and reach the interstitium.

109
Q

Both amphiboles and serpentines are
fibrogenic,and increasing doses are associated with a higher incidence of all asbestos-related
diseases except mesothelioma, which is only associated with amphibole exposure.

T or F

A

True

110
Q

In contrast to other inorganic dusts, asbestos can also act as a tumor initiator and promoter.

T or F

A

True

Some of its oncogenic effects are mediated by reactive free radicals generated by asbestos
fibers, which preferentially localize in the distal lung, close to the mesothelial layers.

Potentially
toxic chemicals adsorbed onto the asbestos fibers most likely contribute to the oncogenicity of
the fibers. For example, the adsorption of carcinogens in tobacco smoke onto asbestos fibers
may well contribute to the remarkable synergy between tobacco smoking and the development
of lung carcinoma in asbestos workers.

One study of asbestos workers found a fivefold
increase of lung carcinoma with asbestos exposure alone,while asbestos exposure and
smoking together led to a 55-fold increase in the risk of lung cancer

111
Q

The occurrence of asbestosis, like the other pneumoconioses, depends on the interaction of
inhaled fibers with lung macrophages and other parenchymal cells.

What is the pathogenesis?

A

The initial injury occurs at
bifurcations of small airways and ducts,where theasbestos fibers land and penetrate.

Macrophages, both alveolar and interstitial, attempt to ingest and clear the fibers and are
activated to release chemotactic factors and fibrogenic mediators that amplify the response.
Chronic deposition of fibers and persistent release of mediators eventually lead to generalized
interstitial pulmonary inflammation and interstitial fibrosis.

112
Q

Asbestosis is marked by diffuse pulmonary interstitial fibrosis, which is
indistinguishable from diffuse interstitial fibrosis resulting from other causes, except for the
presence of multiple asbestos bodies.

A
113
Q

What is the appearance of Asbestos?

A

Asbestos bodies appear as golden brown, fusiform or beaded rods with a translucent center and consist of asbestos fibers coated with an iron-containing proteinaceous material ( Fig. 15-20 ).

They arise when

  • *macrophages attempt to phagocytose asbestos fibers;** the iron is presumably derived from
  • *phagocyte ferritin.**

Other inorganic particulates may become coated with similar iron-protein
complexes and are called ferruginous bodies

. Rare single asbestos bodies can be found in the lungs of normal people.

114
Q

What are ferruginous bodies?

A

Asbestos bodies appear as golden brown, fusiform or beaded rods with a translucent center and consist of asbestos fibers coated with an iron-containing proteinaceous material ( Fig. 15-20 ).

They arise when
macrophages attempt to phagocytose asbestos fibers; theiron is presumably derived from
phagocyte ferritin.

Other inorganic particulates may become coated with similar iron-protein
complexes and are called ferruginous bodies

. Rare single asbestos bodies can be found in the lungs of normal people.

115
Q

Asbestosis begins as ___________

A

fibrosis around respiratory bronchioles and alveolar ducts and extends
to involve adjacent alveolar sacs and alveoli.

The fibrous tissue distorts the architecture,
creating enlarged airspaces enclosed within thick fibrous walls; eventually the affected
regions become honeycombed.

116
Q

The pattern of fibrosis in asbestosis is similar to that seen in UIP, with fibroblastic foci and varying degrees of fibrosis, the onlydifference being the presence of
numerous asbestos bodies.

T or F

A

True

117
Q

What is the difference in asbestosis compared to CWP and silicosis,

A

In contrast to CWP and silicosis, asbestosis begins in the lower lobes and subpleurally.

The middle and upper lobes of the lungs become affected as fibrosis
progresses.

The scarring may trap and narrow pulmonary arteries and arterioles, causing
pulmonary hypertension and cor pulmonale.

118
Q

What is the most common manifestation of asbestos exposure?

A

Pleural plaques, the most common manifestation of asbestos exposure, are wellcircumscribed
plaques of dense collagen( Fig. 15-21 ), oftencontaining calcium.

They
develop most frequently on the anterior and posterolateral aspects of the parietal pleura
and over the domes of the diaphragm.

The size and number of pleural plaques do not
correlate with the level of exposure to asbestos or the time since exposure. [81]

They do not
contain asbestos bodies;however,only rarely do they occur in individuals who have no
history or evidence of asbestos exposure.

Uncommonly, asbestos exposure induces pleural
effusions, which are usually serous but may be bloody. Rarely, diffuse visceral pleural fibrosis
may occur and, in advanced cases, bind the lung to the thoracic cavity wall.

119
Q

Both lung carcinomas and mesotheliomas (pleural and peritoneal) develop in
workers exposed to asbestos

T or F

A

T

Both lung carcinomas and mesotheliomas (pleural and peritoneal) develop in
workers exposed to asbestos.

The risk of lung carcinoma is increased about fivefold for asbestos workers; the relative risk of mesotheliomas, normally a rare tumor (2 to 17 cases per
1 million persons), is more than 1000-fold greater. Concomitant cigarette smoking greatly
increases the risk of lung carcinoma but not that of mesothelioma.

120
Q
A 
FIGURE 15-20 High-power detail of an asbestos body, revealing the typical beading and
knobbed ends (arrow).
121
Q
A

FIGURE 15-21 Asbestos-related pleural plaques. Large, discrete fibrocalcific plaques are
seen on the pleural surface of the diaphragm

122
Q 
The clinical findings in asbestosis are very similar to those caused by other diffuse interstitial
lung diseases (discussed earlier).

What is the first manifestation?

A

Dyspnea is usually the first manifestation; at first, it is
provoked by exertion, but later it is present even at rest.

The dyspnea is usually accompanied
by a cough associated with production of sputum.

These manifestations rarely appear fewer
than 10 years after first exposure and are more common after 20 years or more.

123
Q

Chest x rays of abestosis reaveal?

A

Chest x-rays
reveal irregular linear densities, particularly in both lower lobes.

124
Q

With advancement of the
pneumoconiosis, ___________ develops.

A

a honeycomb pattern

The disease may remain static or progress to
respiratory failure, cor pulmonale, and death.

Pleural plaques are usually asymptomatic and are
detected on radiographs as circumscribed densities. Asbestosis complicated by lung or pleural
cancer is associated with a particularly grim prognosis.

125
Q

Drug-Induced Lung Diseases.

Drugs can cause a variety of both acute and chronic alterations in respiratory structure and
function, interstitial fibrosis, bronchiolitis obliterans, and eosinophilic pneumonia ( Table 15-7
). [82]

For example, ___________cause pulmonary
damage and fibrosis as a result of direct toxicity of the drug and by stimulating the influx of
inflammatory cells into the alveoli.

A

cytotoxic drugs used in cancer therapy (e.g., bleomycin)

126
Q

____, a drug used to treat cardiac arrhythmias, preferentially concentrated in the lung and causes significant pneumonitis in 5% to 15% of
patients receiving it.

A

Amiodarone

127
Q

TABLE 15-7 – Examples of Drug-Induced Pulmonary Disease

Bleomycin

A

Pneumonitis and fibrosis

128
Q

TABLE 15-7 – Examples of Drug-Induced Pulmonary Disease

Methotrexate

A

Hypersensitivity pneumonitis

129
Q

TABLE 15-7 – Examples of Drug-Induced Pulmonary Disease

Amiodarone

A

Pneumonitis and fibrosis

130
Q

TABLE 15-7 – Examples of Drug-Induced Pulmonary Disease

Nitrofurantoin

A

Hypersensitivity pneumonitis

131
Q

TABLE 15-7 – Examples of Drug-Induced Pulmonary Disease

What drugs cause Bronchospasm?

A

Aspirin

β-Antagonists

132
Q

What is Radiation pneumonitis?

A

Radiation pneumonitis is a well-known complication of therapeutic radiation of thoracic tumors
(lung, esophageal, breast, mediastinal). [83]

It most often involves the lung within the radiation
port but occasionally may extend to other areas of the same lung or even the contralateral lung.
It occurs in acute and chronic forms.

133
Q

One to six months after fractionated irradiation,______________occurs in 10% to
20% of patients.

A 
acute
radiation pneumonitis (lymphocytic alveolitis or hypersensitivity pneumonitis)

It is manifest by fever, dyspnea out of proportion to the volume of lung
irradiated, pleural effusion, and radiologic infiltrates that usually correspond to an area of
previous irradiation.

With steroid therapy, these symptoms may resolve completely in some
patients without long-term effects, [84] while in others there is progression to chronic radiation
pneumonitis (pulmonary fibrosis). The latter is a consequence of the repair of injured
endothelial and epithelial cells within the radiation portal

. Morphologic changes are those of
diffuse alveolar damage, including severe atypia of hyperplastic type II cells and fibroblasts.
Epithelial cell atypia and foam cells within vessel walls are also characteristic of radiation
damage.

134
Q

What are the morphologic changes of radiation induced pneumonitis?

A

. Morphologic changes are those of
diffuse alveolar damage, including severe atypia of hyperplastic type II cells and fibroblasts.

135
Q

What are also characteristic of radiation
damage.

A

Epithelial cell atypia and foam cells within vessel walls are also characteristic of radiation
damage.

136
Q

What is sarcoidosis?

A

Sarcoidosis is a systemic disease of unknown cause characterized by noncaseating
granulomas in many tissues and organs.

Sarcoidosis presents many clinical patterns, but

  • **bilateral hilar lymphadenopathy or lung involvement is visible on chest radiographs in 90% of
    cases. ***

Eye and skin lesions occur next in frequency.

Since other diseases, including
mycobacterial and fungal infections and berylliosis, can also produce noncaseating (hard)
granulomas, the histologic diagnosis of sarcoidosis is made by exclusion. [85]

The prevalence of sarcoidosis is higher in women than in men but varies widely in different
countries and populations.

In the United States the rates are highest in the Southeast; they are
10 times higher in American blacks than in whites.

In contrast, the disease is rare among
Chinese and Southeast Asians.

137
Q

Sarcoidosis presents many clinical patterns, but
90% occurs on these two organs visible on chest radiograph.

A

bilateral hilar lymphadenopathy or lung involvement is visible on chest radiographs in 90% of
cases.

138
Q

Although the etiology of sarcoidosis remains unknown, several lines of evidence suggest that it
is a disease of disordered immune regulation in genetically predisposed individuals exposed to
certain environmental agents.[86]

The role of each of these three contributory factors is
summarized below.

A
  • Immunological Factors.
  • Genetic Factors.
  • Environmental Factors.
139
Q

There are several immunological abnormalities in the local milieu of sarcoid granulomas that
suggest the development of a cell-mediated response to an unidentified antigen. [87] The
process is driven by CD4+ helper T cells. These abnormalities include [88] :

A
  • Intra-alveolar and interstitial accumulation of CD4+ T cells, resulting in CD4/CD8 T-cellratios ranging from 5 : 1 to 15 : 1. There is oligoclonal expansion of T-cell subsets as determined by analysis of T-cell receptor rearrangement, suggesting an antigen-driven proliferation.
  • Increased levels of T cell–derived TH1 cytokines such as IL-2 and IFN-γ, resulting in Tcell expansion and macrophage activation, respectively.
  • Increased levels of several cytokines in the local environment (IL-8, TNF, macrophage inflammatory protein 1α) that favor recruitment of additional T cells and monocytes and contribute to the formation of granulomas. TNF in particular is released at high levels by activated alveolar macrophages, and the TNF concentration in the bronchoalveolar fluid is a marker of disease activity.
140
Q

Additionally, there are systemic immunological abnormalities in individuals with sarcoidosis:

A

• Anergy to common skin test antigens such as Candida or tuberculosis purified protein
derivative (PPD)
• Polyclonal hypergammaglobulinemia, another manifestation of helper T-cell dysregulation.

141
Q

Genetic Factors.

Evidence of genetic influences are the familial and racial clustering of cases and the association with certain ____________

A

HLA genotypes (e.g., HLA-A1 and HLA-B8).

142
Q

These are possibly the most tenuous of all the associations in the pathogenesis of sarcoidosis.

A

Environment factors

As with many other diseases of unknown etiology, suspicion falls on microbes.

Indeed several
putative microbes have been proposed as the inciting agent for sarcoidosis (e.g., mycobacteria,
Propionibacterium acnes, and Rickettsia species). [89] Alas there is no unequivocal evidence
that sarcoidosis is caused by an infectious agent

143
Q

What is the histological apperance of sarcoidosis?

A

Histologically, all involved tissues show the classic well-formed noncaseating
granulomas( Fig. 15-22 ), each composed of an aggregate of tightly clustered epithelioid
cells, often with Langhans or foreign body–type giant cells.

Central necrosis is unusual.

With
chronicity the granulomas may become enclosed within fibrous rims or may eventually be
replaced by hyaline fibrous scars.

Laminated concretions composed of calcium and proteins
known as Schaumann bodies and stellate inclusions known as asteroid bodies enclosed
within giant cells are found in approximately 60% of the granulomas.

Though characteristic,
these microscopic features are notpathognomonic of sarcoidosis, because asteroid and
Schaumann bodies may be encountered in other granulomatous diseases (e.g.,
tuberculosis).

Pathologic involvement of virtually every organ in the body has been cited at
one time or another

144
Q

What are Schaumann bodies and stellate inclusions ?

A

.

Laminated concretions composed of calcium and proteins
known as Schaumann bodiesandstellate inclusions known as asteroid bodies enclosed
within giant cells are found in approximately 60% of the granulomas.

Though characteristic,
these microscopic features are notpathognomonic of sarcoidosis, because asteroid and
Schaumann bodies may be encountered in other granulomatous diseases (e.g.,
tuberculosis).

Pathologic involvement of virtually every organ in the body has been cited at
one time or another

145
Q

What is the common site of involvementi in sarcoidosis?

A

The lungs are common sites of involvement. [90]

Macroscopically there is usually no
demonstrable alteration, although in advanced casesthe coalescence of granulomas
produces small nodules that are palpable or visible as 1 to 2 cm, noncaseating, noncavitated
consolidations.

Histologically, the lesions are distributed primarily along the lymphatics,
around bronchi and blood vessels, although alveolar lesions are also seen.

The relative
frequency of granulomas in the bronchial submucosa accounts for the high diagnostic yield of
bronchoscopic biopsies.

There seems to be a strong tendency for lesions to heal in the lungs,
so varying stages of fibrosis and hyalinization are often found.

The pleural surfaces are
sometimes involved

146
Q

In sarcoidosis Lymph nodes are involved in almost all cases, particularly the hilar and mediastinal nodes,
but any other node in the body may be involved.

Nodes are characteristically enlarged,
discrete, and sometimes calcified.

The tonsils are affected in about one quarter to one third of
cases.

A
147
Q

In Sarcoidosis, the spleen is affected microscopically in about three quarters of cases, but it is enlarged in
only one fifth.

On occasion, granulomas may coalesce to form small nodules that are barely
visible macroscopically.

The capsule is not involved.

The liver is affected slightly less often
than the spleen. It may also be moderately enlarged and contains scattered granulomas,
more in portal triads than in the lobular parenchyma. Needle biopsy can be diagnostic.

A
148
Q

The bone marrow is involved in about one fifth of cases of systemic sarcoidosis.

The

radiologically visible bone lesions have a particular tendency to involve phalangeal bones of

the hands and feet, creating small circumscribed areas of bone resorption within the marrow

cavity and a diffuse reticulated pattern throughout the cavity, with widening of the bony shafts

or new bone formation on the outer surfaces

A
149
Q

Skin lesions are encountered in one third to one half of cases.

Sarcoidosis of the skin
assumes a variety of macroscopic appearances (e.g., discrete subcutaneous nodules; focal,
slightly elevated, erythematous plaques; or flat lesions that are slightly reddened and scaling,
and resemble those of lupus erythematosus). Lesions may also appear on the mucous
membranes of the oral cavity, larynx, and upper respiratory tract

A
150
Q

The eye, its associated
glands, and the salivary glands are involved in about one fifth to one half of cases.

The
ocular involvement takes the form of iritis or iridocyclitis, either bilaterally or unilaterally.

Consequently, corneal opacities, glaucoma, and total loss of vision may occur.

These ocular
lesions are frequently accompanied by inflammation of the lacrimal glands, with suppression
of lacrimation.

A
151
Q

What is the Mikulicz syndrome?

A

Bilateral sarcoidosis of the parotid, submaxillary, and sublingual glands
constitutes the combined uveoparotid involvement designated as Mikulicz syndrome

152
Q

Muscle involvement is often underdiagnosed, since it may be asymptomatic

. Muscle
weakness, aches, tenderness, and fatigue should prompt consideration of occult sarcoid
myositis. [91]

Muscle biopsy can be useful for diagnosis when clinical features point to
sarcoidosis.

Sarcoid granulomas occasionally occur in the heart, kidneys, central nervous
system, and endocrine glands, particularly in the pituitary, as well as in other body tissues.

A
153
Q

Because of its varying severity and the inconstant distribution of the lesions, sarcoidosis is a
_____________

A

protean clinical disease.

It may be discovered unexpectedly on routine chest films as bilateral
hilar adenopathy or may present with peripheral lymphadenopathy, cutaneous lesions, eye
involvement,splenomegaly, or hepatomegaly.

In the great majority of cases, however,
individuals seek medical attention because of the insidious onset of respiratory abnormalities
(shortness of breath, cough, chest pain, hemoptysis) or of constitutional signs and symptoms
(fever, fatigue, weight loss, anorexia, night sweats).

154
Q

Sarcoidosis follows an unpredictable course characterized by either progressive chronicity or
periods of activity interspersed with remissions, sometimes permanent, that may be
spontaneous or induced by steroid therapy.

Overall, 65% to 70% of affected patients recover
with minimal or no residual manifestations.

Twenty percent have permanent loss of some lung
function or some permanent visual impairment. Of the remaining 10% to 15%, some die of
cardiac or central nervous system damage, but most succumb to progressive pulmonary
fibrosis and cor pulmonale

A
155
Q

What is hypersensitivity pneumonitis?

A

The term hypersensitivity pneumonitis describes a spectrum of immunologically mediated,
predominantly interstitial, lung disorders caused by intense, often prolonged exposure to inhaled organic antigens. [92]

Affected individuals have an abnormal sensitivity or heightened
reactivity to the antigen, which,in contrast to that occurring in asthma, involves primarily the
alveoli (thus the synonym “allergic alveolitis”).

[93] It is important to recognize these diseases
early in their course because progression to serious chronic fibrotic lung disease can be
prevented by removal of the environmental agent.

156
Q

What is the difference between hypersensitivy pneumonitis over asthma?

A

Affected individuals have an abnormal sensitivity or heightened
reactivity to the antigen, which, in contrast to that occurring in asthma, involves primarily the
alveoli (thus the synonym “allergic alveolitis”).

157
Q

Most commonly, hypersensitivity results from the inhalation of organic dust containing antigens
made up of spores of thermophilic bacteria, true fungi, animal proteins, or bacterial products.

Numerous specifically named syndromes are described, depending on the occupation or
exposure of the individual.

Farmer’s lung results from exposure to dusts generated from harvested humid, warm hay that permits the rapid proliferation of the spores of thermophilic
actinomycetes.

Pigeon breeder’s lung (bird fancier’s disease) is provoked by proteins from
serum, excreta, or feathers of birds. Humidifier or air-conditioner lung is caused by thermophilic
bacteria in heated water reservoirs

A
158
Q

Several lines of evidence suggest that hypersensitivity pneumonitis is an immunologically
mediated disease:

A
  • Bronchoalveolar lavage specimens obtained during the acute phase show increased levels of proinflammatory chemokines such as macrophage inflammatory protein 1α and IL-8.
  • Bronchoalveolar lavage specimens also consistently demonstrate increased numbers of T lymphocytes of both CD4+ and CD8+ phenotypes.
  • Most patients have specific antibodies in their serum, a feature that is suggestive of type III (immune complex) hypersensitivity.
  • Complement and immunoglobulins have been demonstrated within vessel walls by immunofluorescence, also indicating a type III hypersensitivity
159
Q

Finally, the presence of noncaseating granulomas in two thirds of the patients with hypersensitivity pneumonitis suggests the
development of a ____________

A

T cell–mediated (type IV) delayed-type hypersensitivity against the implicated
antigen(s).

160
Q

Histologic changes in subacute and chronic forms are characteristically
centered on bronchioles.

[94] They include :

A

Histologic changes in subacute and chronic forms are characteristically
centered on bronchioles. [94] They include

  • (1) interstitial pneumonitis consisting primarily of lymphocytes, plasma cells, and macrophages
  • (2) noncaseating granulomas in two thirds of patients ( Fig. 15-23 ); and
  • (3) interstitial fibrosis, honeycombing, and obliterative bronchiolitis (in late stages)

​

​​

In more than half the patients there is also evidence of an intra-alveolar infiltrate.

161
Q
A

FIGURE 15-23 Hypersensitivity pneumonitis, histologic appearance. Loosely formed
interstitial granulomas and chronic inflammation are characteristic

162
Q

What is the clinical manifestation of hypersensitivity pneumonitis?

A

The clinical manifestations are varied.

Acute attacks, which follow inhalation of antigenic dust insensitized patients, consist of recurring episodes of fever, dyspnea, cough, and leukocytosis.

  • *Diffuse and nodular infiltrates appear in the chest radiograph, and pulmonary function tests**
  • *show an acute restrictive disorder**

. Symptoms usually appear 4 to 6 hours after exposure

If exposure is continuous and protracted, a chronic form of the disease supervenes with progressive respiratory failure, dyspnea, and cyanosis and a decrease in total lung capacity and compliance—a picture similar to other forms of chronic interstitial disease.

163
Q

What is PULMONARY EOSINOPHILIA ?

A

Several clinical and pathologic pulmonary entities are characterized by an infiltration of
eosinophils, recruited in part by elevated alveolar levels of eosinophil attractants such as IL- 5.

164
Q

Pulmonary eosinophilia is divided into the following categories [96] :

A
  • Acute eosinophilic pneumonia with respiratory failure
  • Simple pulmonary eosinophilia or Löffler syndrome
  • Tropical eosinophilia, caused by infection with microfilariae
  • Secondary eosinophilia (which occurs in a number of parasitic, fungal, and bacterial infections; in hypersensitivity pneumonitis; in drug allergies; and in association with asthma, allergic bronchopulmonary aspergillosis, or vasculitis)
  • So-called idiopathic chronic eosinophilic pneumonia
165
Q

What is Acute eosinophilic pneumonia ?

A
166
Q

What is Simple pulmonary eosinophilia ?

A

Simple pulmonary eosinophilia is characterized by transient pulmonary lesions, eosinophilia in
the blood, and a benign clinical course.

CT scans are often quite striking, with shadows of
varying size and shape in any of the lobes, suggesting irregular intrapulmonary densities.

The
alveolar septa are thickened by an infiltrate composed of eosinophils and occasional
interspersed giant cells, but there is no vasculitis, fibrosis, or necrosis.

167
Q

What is Chronic eosinophilic pneumonia ?

A

Chronic eosinophilic pneumonia is characterized by focal areas of cellular consolidation of the
lung substance distributed chiefly in the periphery of the lung fields.

Prominent in these lesions
are heavy aggregates of lymphocytes and eosinophils within both the septal walls and the
alveolar spaces.

These patients have high fever, night sweats, and dyspnea, all of which respond to corticosteroid therapy.

168
Q

SMOKING-RELATED INTERSTITIAL DISEASES

A
  • Desquamative Interstitial Pneumonia
  • Respiratory Bronchiolitis-Associated Interstitial Lung Disease
169
Q

What is “desquamative interstitial pneumonia.”?

A

The large collections of airspace macrophages that char-acterize DIP were originally thought to
be desquamated pneumocytes, thus the misnomer “desquamative interstitial pneumonia.”

170
Q

What is The most striking histologic finding in DIP?

A

The most striking histologic finding is the accumulation of a large number of

  • *macrophages with abundant cytoplasm containing dusty brown pigment (smokers’**
  • *macrophages) in the airspaces.**

Finely granular iron may be seen in the macrophage
cytoplasm.

Some of the macrophages contain lamellar bodies (composed of surfactant) within
phagocytic vacuoles, presumably derived from necrotic type II pneumocytes.

The alveolar

  • *septa are thickened by a sparse inflammatory infiltrate of lymphocytes, plasma cells, and**
  • *occasional eosinophils** ( Fig. 15-24 ).

The septa are lined by plump, cuboidal pneumocytes.
Interstitial fibrosis, when present, is mil]d.

Emphysema is often present.

171
Q
A

FIGURE 15-24 Desquamative interstitial pneumonia. Medium-power detail of lung
demonstrates the accumulation of large numbers of macrophages within the alveolar
spaces and only mild fibrous thickening of the alveolar walls.
DIP

172
Q

DIP usually presents in the fourth or fifth decade of life, and is more common in women than in
men by a ratio of 2 : 1.

Virtually all patients are cigarette smokers.

T or F

A

DIP usually presents in the fourth or fifth decade of life, and is more common in men than in
women by a ratio of 2 : 1.

Virtually all patients are cigarette smokers.

173
Q

What is Respiratory Bronchiolitis-Associated Interstitial Lung Disease ?

A

Respiratory bronchiolitis is a common histologic lesion found in cigarette smokers.

It is
characterized by the presence of pigmented intraluminal macrophages within first- and secondorder
respiratory bronchioles.

In its mildest form, it is seen most often as an incidental histologic
finding in the lungs of smokers or ex-smokers. [99] The term respiratory bronchiolitisassociated
interstitial lung disease is ualitiesed for patients who develop significant pulmonary

symptoms, abnormal pulmonary function, and imaging abnorms.

174
Q

What is the histological morphology of Respiratory Bronchiolitis-Associated Interstitial Lung Disease

A

The changes are patchy at low magnification and have a bronchiolocentric distribution.

Respiratory bronchioles, alveolar ducts, and peribronchiolar spaces contain
aggregates of dusty brown macrophages (smokers’ macrophages) similar to those seen in
DIP. There is a patchy submucosal and peribronchiolar infiltrate of lymphocytes and
histiocytes.

Mild peribronchiolar fibrosis is also seen, which expands contiguous alveolar
septa.

Centrilobular emphysema is common but not severe. Histologic overlap with DIP is often found in different parts of the same lung.

175
Q

What are the symptoms of Respiratory Bronchiolitis-Associated Interstitial Lung Disease?

A

Symptoms are usually mild, consisting of gradual onset of dyspnea and cough in patients who
are typically current smokers in the fourth or fifth decade of life with average exposures of over
30 pack-years of cigarette smoking.

There is a 2 : 1 male predominance.

Cessation of smoking
usually results in improvement.

176
Q

What is PULMONARY ALVEOLAR PROTEINOSIS?

A

Pulmonary alveolar proteinosis (PAP) is a rare disease that is characterized radiologically by
bilateral patchy asymmetric pulmonary opacificationsandhistologically by accumulation of
acellular surfactant in the intra-alveolar and bronchiolar spaces

177
Q

PULMONARY ALVEOLAR PROTEINOSIS has three distinct
classes of this disease—__________—each with a different
pathogenesis but with a similar spectrum of histologic changes.

A

acquired, congenital, and secondary PAP

178
Q

What is acquired PAP?

A

Acquired PAP represents 90% of all cases of PAP and lacks any familial predisposition.
Unexpectedly, researchers working with knockout mice lacking the gene for the hematopoietic
growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) found that these
mice had impaired surfactant clearance by alveolar macrophages, leading to a condition that
resembled human PAP.

179
Q

What is the pathophysio of Acquired PAP?

A

Subsequently, a GM-CSF–neutralizing autoantibody was found in the
serum and bronchial fluid of individuals with acquired PAP that was not present in those with
congenital or secondary PAP.

Currently, it is thought that the anti–GM-CSF antibody is
responsible for the development of the disease. [100] These antibodies inhibit the activity of
endogenous GM-CSF, leading to a state of functional GM-CSF deficiency.

The systemic
production of the antibody also provides an explanation for the recurrence of PAP following
bilateral-lung transplantation.

Thus, acquired PAP is an autoimmune disorder

180
Q

acquired PAP is an autoimmune disorder

T or F

A

True

181
Q

What is congenital PAP?

A

Congenital PAP is a rare cause of immediate-onset neonatal respiratory distress.

182
Q

What is the pathophysiology of congenital PAP

A

Congenital PAP is a rare cause of immediate-onset neonatal respiratory distress.

Thus far,
mutations have been identified in multiple genes including those encoding ATP-binding cassette
protein member A3 (ABCA3)(which may be the most frequent),surfactant protein B (SP-B),
surfactant protein C (SP-C), GM-CSF, and GM receptor (GM-CSF/IL-3/IL-5) β chain.

ABCA3 is
localized to the lamellar body membrane andis probably involved in transport of surfactant
components. [101]

SP-B deficiency is transmitted in an autosomal recessive manner and is
most often caused by a frameshift mutation in the SP-B gene.

This leads to an unstable SP-B
messenger RNA, reduced or absent SP-B, secondary disturbances of SP-C, and intra-alveolar
accumulation of SP-A and SP-C.

183
Q

what is the most frequent mutation inf congenital PAP?

A

protein member A3 (ABCA3)

184
Q

What is secondary PAP?

A

Secondary PAP is uncommon.

The underlying causes include hematopoietic disorders,
malignancies, immunodeficiency disorders, lysinuric protein intolerance, and acute silicosis and
other inhalational syndromes.

185
Q

Whta is the characteristic of PAP?

A

The disease is characterized by a peculiar homogeneous, granular precipitate

  • *within the alveoli, causing focal-to-confluent consolidation** of large areas of the lungs with
  • *minimal inflammatory reaction** ( Fig. 15-25 ).

On section, turbid fluid exudes from these areas.
As a consequence there is a marked increase in the size and weight of the lung.

The alveolar
precipitate is periodic acid–Schiff positive and also contains cholesterol clefts.
Immunohistochemical stains show the presence of surfactant proteins A and C in congenital
SP-B deficiency and all three proteins in the acquired form. Ultrastructurally, abnormalities in
lamellar bodies in type II pneumocytes can be seen in mutations of SP-B, SP-C, and
ABCA3.

186
Q
A

FIGURE 15-25 Pulmonary alveolar proteinosis, histologic appearance. The alveoli are
filled with a dense, amorphous, protein-lipid granular precipitate, while the alveolar walls
are normal.

187
Q

What is the presentation of PAP?

A

Adult patients, for the most part, present with nonspecific respiratory difficulty of insidious onset,
cough, and abundant sputum that often contains chunks of gelatinous material.

Some have
symptoms lasting for years, often with febrile illnesses.

These patients are at risk for developing
secondary infections with a variety of organisms.

Progressive dyspnea, cyanosis, and
respiratory insufficiency may occur, but some patients tend to have a benign course, with
eventual resolution of the lesions. Whole-lung lavage remains the current standard of care,
while GM-CSF therapy is effective in 50% of patients

188
Q

Congenital PAP is a disorder of?

A

Congenital PAP is a fatal respiratory disorder that is usually immediately apparent in the
newborn.

Typically, the infant is full term and rapidly develops progressive respiratory distress
shortly after birth.

Without lung transplantation, death ensues between 3 and 6 months of age.

189
Q
A

FIGURE 15-22 Characteristic sarcoid noncaseating granulomas, peribronchial, with many
giant cells.

190
Q
A

2H Sytem Patho: LUNGS (11 decks)

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