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

Question

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

Answer 1

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.***

Answer 2

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

Answer 3

**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)***

Answer 4

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

Answer 5

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

Answer 6

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.**

Answer 7

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 disease**with a**rapid downhill clinical course**. The **mean survival is 3 years** or less. Lung transplantation is the only definitive therapy currently available.

Answer 8

**Lung transplantation** is the only definitive therapy currently available.

Answer 9

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**

Answer 10

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.

Answer 11

* cellular and * fibrosing patterns

Answer 12

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.***

Answer 13

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 s***ome 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

Answer 14

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 outcome**than do those with fibrosing pattern and UIP

Answer 15

Cryptogenic organizing pneumonia is synonymous with the popular term ***bronchiolitis obliterans organizing pneumonia;***however, the**former is now preferred,****since it conveys the essential features of a clinicopathologic syndrome**of unknown**etiology and avoids confusion with airway diseases such as bronchiolitis obliterans.** ## Footnote **Patients present with cough and dyspnea and have subpleural or peribronchial patchy areas of airspace consolidation radiographically**

Answer 16

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.**

Answer 17

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

Answer 18

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

Answer 19

Many connective tissue diseases, notably **systemic lupus erythematosus, rheumatoid arthritis, progressive systemic sclerosis (scleroderma), dermatomyositis-polymyositi**s, 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.

Answer 20

* systemic lupus erythematosus, * rheumatoid arthritis, * progressive systemic sclerosis (scleroderma), * dermatomyositis-polymyositis, and * mixed connective tissue disease

Answer 21

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

Answer 22

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

Answer 23

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

Answer 24

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

Answer 25

The term pneumoconiosis was originally coined to describe th**e 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 particulates**and**chemical 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.

Answer 26

* MINERAL DUSTS * ORGANIC DUSTS THAT INDUCE HYPERSENSITIVITY PNEUMONITIS * ORGANIC DUSTS THAT INDUCE ASTHMA * CHEMICAL FUMES AND VAPORS

Answer 27

* Coal dust * Silica * Asbestos * Beryllium * Iron oxide * Barium sulfate * Tin oxide

Answer 28

* Moldy hay * Bagasse * Bird droppings

Answer 29

* Cotton, flax, hemp * Red cedar dust

Answer 30

* Nitrous oxide, * sulfur dioxide, * ammonia, * benzene, * insecticides

Answer 31

* Anthracosis Coal mining (particularly hard coal) * Macules * Progressive massive fibrosis * Caplan syndrome

Answer 32

* Silicosis * Caplan syndrome

Answer 33

* Asbestosis * Pleural plaques * Caplan syndrome * ***Mesothelioma*** * **Carcinoma of the lung, larynx, stomach, colon**

Answer 34

* Acute berylliosis * Beryllium granulomatosis * Lung carcinoma

Answer 35

Siderosis Exposure Welding

Answer 36

Baritosis Which is an exposure from mining?

Answer 37

Stannosis Exposure from Mining

Answer 38

Farmer's lung from farming

Answer 39

Bagassosis from Manufacturing wallboard, paper

Answer 40

Bird-breeder's lung From Bird handling

Answer 41

Byssinosis

Answer 42

* Bronchitis, asthma * Pulmonary edema * ARDS * Mucosal injury * Fulminant poisoning From occupational and accidental exposure

Answer 43

(1) the **amount of dust retaine**d in the lung and airways; (2) the **size, shape, and therefore buoyanc**y of the particles; (3) **particle solubility** and physiochemical reactivity; and (4) the **possible additional effects of other irritants** (e.g., concomitant tobacco smoking).

Answer 44

**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.

Answer 45

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.

Answer 46

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

Answer 47

* (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]

Answer 48

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.

Answer 49

. 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.

Answer 50

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**.

Answer 51

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.**

Answer 52

``` 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 cm**in**greatest diamete**r. 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.**

Answer 53

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.

Answer 54

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).

Answer 55

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

Answer 56

Of these, quartz is most commonly implicated in silicosis.

Answer 57

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.

Answer 58

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

Answer 59

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).

Answer 60

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.

Answer 61

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**

Answer 62

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

Answer 63

FIGURE 15-19 Several coalescent collagenous silicotic nodules.

Answer 64

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.

Answer 65

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.

Answer 66

* **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.

Answer 67

central zone of caseation.

Answer 68

* 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

Answer 69

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

Answer 70

* serpentine and * amphibole

Answer 71

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

Answer 72

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

Answer 73

aerodynamic properties and solubility

Answer 74

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.**

Answer 75

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.

Answer 76

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**

Answer 77

The **initial injury occurs at bifurcations of small airways and ducts,**where the**asbestos fibers land and penetrate.** Macrophages, **both alveolar and interstitial, attempt to ingest and clear the fibers and are activated to release chemotactic factor**s 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.**

Answer 78

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.

Answer 79

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 materia**l ( 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.

Answer 80

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.**

Answer 81

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.**

Answer 82

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

Answer 83

**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.

Answer 84

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

Answer 85

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

Answer 86

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.

Answer 87

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

Answer 88

a honeycomb pattern The disease may remain static or progress to respiratory failure, cor pulmonale, and death. **Pleural plaques are usually asymptomati**c and are **detected on radiographs as circumscribed densities.** Asbestosis complicated by lung or pleural cancer is associated with a particularly grim prognosis.

Answer 89

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

Answer 90

Amiodarone

Answer 91

Pneumonitis and fibrosis

Answer 92

Hypersensitivity pneumonitis

Answer 93

Pneumonitis and fibrosis

Answer 94

Hypersensitivity pneumonitis

Answer 95

Aspirin β-Antagonists

Answer 96

Radiation pneumonitis is a well-known complication of therapeutic radiation of t**horacic 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.

Answer 97

``` 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.**

Answer 98

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

Answer 99

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

Answer 100

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 d**isease is rare among Chinese and Southeast Asians.**

Answer 101

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

Answer 102

* Immunological Factors. * Genetic Factors. * Environmental Factors.

Answer 103

* 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.

Answer 104

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

Answer 105

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

Answer 106

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

Answer 107

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

Answer 108

. **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 sarcoidosi**s, 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

Answer 109

The **lungs are common sites of involvement**. [90] **Macroscopically there is usually no demonstrable alteration**, although in advanced cases**the 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**

Answer 110

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

Answer 111

**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).**

Answer 112

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

Answer 113

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”).***

Answer 114

* 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

Answer 115

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

Answer 116

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.

Answer 117

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

Answer 118

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.

Answer 119

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.**

Answer 120

* 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**

Answer 121

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.

Answer 122

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.**

Answer 123

* Desquamative Interstitial Pneumonia * Respiratory Bronchiolitis-Associated Interstitial Lung Disease

Answer 124

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

Answer 125

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.

Answer 126

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

Answer 127

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**. ## Footnote **Virtually all patients are cigarette smokers.**

Answer 128

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.**

Answer 129

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.

Answer 130

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.

Answer 131

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

Answer 132

acquired, congenital, and secondary PAP

Answer 133

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.

Answer 134

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

Answer 135

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

Answer 136

Congenital PAP is a r**are 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.

Answer 137

protein member A3 (ABCA3)

Answer 138

Secondary PAP is uncommon. The underlying causes include **hematopoietic disorders,** **malignancies, immunodeficiency disorders, lysinuric protein intolerance, and acute silicosis and other inhalational syndromes.**

Answer 139

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.

Answer 140

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.

Answer 141

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 s**ymptoms 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

Answer 142

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.

Answer 143

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