Diffuse Interstitial (Restrictive) Lung Diseases

Question 1

Acute Lung Injury

Answer 1

a condition characterized by:

1) an abrupt decline in respiratory function
2) bilateral infiltrates
3) reduced lung compliance
4) hypoxemia, in the
5) absence of heart failure. T

his condition may be caused by a wide variety of agents that diffusely injure the delicate lung parenchyma (e.g. sepsis, aspiration, infections, trauma, radiation, inhalation of toxic agents, drug reactions, etc.). Other times, the cause of ALI is idiopathic, for which the term “acute interstitial pneumonia (AIP)” is used.

Question 2

Acute Respiratory Distress Syndrome

Answer 2

ARDS is a clinical syndrome characterized by severe acute respiratory failure, and is a manifestation of severe ALI.

*NOTE: Although all ARDS falls under the larger umbrella term of ALI, not all ALI is severe enough to result in ARDS.

Question 3

4 Most Common Causes of ALi and ARDS

Answer 3

1. Sepsis
2. Diffuse infections
3. Aspiration.
4. Trauma.

Question 4

Diffuse Alveolar Damage

Answer 4

DAD is a pathologic term and is the histologic manifestation of severe acute lung injury (ALI), and generally occurs in association with clinical ARDS.

Question 5

DAD Gross Appearance

Answer 5

Very heavy lungs, diffusely firm, and red-tan.

Question 6

Microscopic Appearance DAD

Answer 6

• Diffuse damage to all parts of the alveolar wall, including epithelial and endothelial cell injury.
• Formation of “hyaline membranes” on the surface of the damaged alveolar ducts/alveoli.
• Hyperplasia of type II pneumocytes.
• Granulation tissue formation (“organization”) with influx of lymphocytes, macrophages, and fibroblasts.

Question 7

Pathogenesis of DAD

Answer 7

The pathogenesis of DAD includes a combination of endothelial injury with endothelial activation, recruitment of neutrophils, accumulation of fluid in alveolar spaces with formation of hyaline membranes, and release of cytokines that perpetuate the inflammatory response

Question 8

Treatment of ALI/ARDS

Answer 8

No proven treatments are available. Despite this grim reality, treatment usually includes:

1. Mechanical ventilation–oxygen.
2. Supportive care.
3. Treatment of underlying causes, such as sepsis.

Question 9

Prognosis of ALI/ARDS

Answer 9

1. 40-50% of patients recover, with normal lung function.
2. Many patients die acutely, especially with ARDS.
3. A few patients develop diffuse fibrosis and die in weeks to months.

Question 10

Restrictive Lung Disease Definition

Answer 10

A broad category of diffuse lung disease characterized by reduced expansion of lung parenchyma. This may occur in two settings:

1) diffuse diseases of the interstitium, such as pulmonary fibrosis (interstitial scarring), and
2) chest wall disease with normal lungs (e.g. obesity, pleural diseases, neuromuscular diseases).

• Over time, this usually results in decreased total lung volume, but airflow is normal or reduced proportionally.

Question 11

Idiopathic Pulmonary Fibrosis

Answer 11

• A specific clinical syndrome of unknown cause, characterized by relentlessly progressive interstitial fibrosis of the lungs and respiratory failure, associated with the specific pathologic pattern of fibrosis called “usual interstitial pneumonia” (UIP).
• Usual interstitial pneumonia (UIP): A specific pathologic pattern of fibrosis, characterized by heterogeneous and peripherally accentuated fibrosis. This pattern may be seen in the setting of IPF if its cause is idiopathic, but the UIP pattern may also be seen in other non-idiopathic conditions.

Question 12

Clinical Characteristics of IPF

Answer 12

1. Fibrosis in IPF only involves the lungs.
2. IPF involves men more than women.
3. IPF usually occurs in older adults and elderly; rarely appears before age 50.
4. Smoking and exposures to metal fumes, wood dust, and other occupational irritants increases risk of developing IPF.
5. Familial forms occur, associated with various gene mutations.
6. Prognosis is worse than for all other types of chronic interstitial lung disease. Patients experience a progressive gradual decline in lung function, sometimes interspersed by abrupt (and permanent) rapid declines in lung function (“acute exacerbations”); most patients die within 3-45 years after initial diagnosis, despite all treatments available, although recently approved drugs have offered a glimmer of hope.

Question 13

Pathogenesis of IPF

Answer 13

1. Unknown cause, but a peculiar immune mechanism is suspected.
2. Unregulated fibrosis rather than inflammation is the problem.
3. Mediators are released that cause fibroblasts to proliferate and lay down collagen.
4. Unknown stimulus continues relentlessly, so disease progresses to death, usually within 3 to 5 years.

Question 14

Gross Pathology of IPF

Answer 14

Gross pathology and the UIP pattern:

1. Lungs are usually smaller than normal.
2. Pleura is diffusely bumpy (“cobblestoned”).
3. Firm strands of fibrous tissue in peripheral (subpleural) lung zones, particularly in lower lobes.
4. Dilated air spaces surrounded by dense fibrous tissue may occur, often occurring in groups (called “honeycombing” because of its resemblance to a beehive’s honeycomb).

Question 15

Microscopic Features of the UIP Pattern

Answer 15

1. Patchy destruction of lung architecture because of dense fibrosis; process is accentuated at the periphery of lobules and under the pleura, but other areas are completely spared (“spatial heterogeneity”).
2. Areas of dense mature (old) fibrosis adjacent to foci of loose immature (new) fibrosis with proliferating fibroblasts, called fibroblast foci (“temporal heterogeneity”).

*NOTE: Although IPF is characterized pathologically by the presence of fibrosis in a UIP pattern, this UIP pattern can also be seen in other nonidiopathic conditions. IPF by definition is idiopathic; if UIP is observed, a clinical diagnosis of IPF is only made after excluding other known causes of a UIP pattern!

Question 16

Nonspecific Interstitial Pneumonia

Answer 16

Nonspecific interstitial pneumonia (NSIP) is a chronic fibrosing interstitial lung disease that lacks characteristics of the other wellcharacterized (specific) diseases. It can be idiopathic, or may occur in the setting of an underlying connective tissue disease.

Question 17

Characteristics of NSIP

Answer 17

1. A disease of adults, especially women.
2. Pathology shows a pattern of diffuse homogeneous thickening of alveolar walls by lymphocytes and fibrosis.
3. Prognosis is much better than IPF.
4. Patients may get better (70%), remain stable (20%), or in a minority of cases progress to end-stage fibrosis or other fatal complications.

Question 18

Cryptogenic Organizing Pneumonia

Answer 18

Cryptogenic organizing pneumonia (COP) is a restrictive lung disease of unknown (idiopathic or cryptogenic) cause, characterized by injury to the lung that results in filling of alveoli and terminal bronchioles by plugs of proliferating fibroblasts (“organization”).

Question 19

Characteristics of COP

Answer 19

1. Old term for this disorder was “bronchiolitis obliterans organizing pneumonia” (BOOP); however, this catchy term should no longer used as it leads to confusion with bronchiolitis obliterans, a completely different disease of the small airways that is unrelated to COP.
2. Good prognosis, because there is no mature fibrosis.
3. Steroids are often used to treat COP.

Question 20

Connective Tissue Disease-Associated Interstitial Lung Disease

Answer 20

Certain connective tissue diseases can cause fibrosis of the lungs if they are poorly controlled, a feared complication of these disorders. When the lungs become involved in these disorders, fibrosis ensues that often has a pathologic pattern of either UIP or NSIP. Prevention or slowing of the disease is generally achieved by controlling the underlying connective tissue disease with steroids and immunomodulatory agents. Examples of connective tissue diseases that can cause lung fibrosis:

1. Rheumatoid arthritis.*
2. Scleroderma / progressive systemic sclerosis.
3. Polymyositis / dermatomyositis.
4. Sjögren syndrome.
5. Mixed connective tissue disease (MCTD).

*NOTE: Rheumatoid arthritis can also produce an acute or chronic pleuritis, rheumatoid nodules in the lungs, DAD, bronchiolitis, and Caplan nodules (Caplan syndrome) when associated with silicosis or coal workers’ pneumoconiosis.

Question 21

Drug Induced Lung Disease

Answer 21

Some drugs produce various forms of interstitial lung disease, particularly antineoplastic drugs.

1. The disease may produce patterns of injury or fibrosis that look histologically like DAD, UIP, NSIP, organizing pneumonia, granulomatous disease, or other patterns.
2. The injury may be dose dependent or simply an idiosyncratic reaction.
3. This complication is treatable if recognized in time; treatment requires cessation of the offending agent.

Question 22

Sarcoidosis

Answer 22

: Sarcoidosis is a multisystem granulomatous disease of unknown cause, characterized by granulomatous inflammation and fibrosis of affected organs; the lung is very commonly involved.

Question 23

Characteristics of Sarcoidosis

Answer 23

1. Worldwide disease with increased frequency in certain areas, and much more common in African-American individuals; rare among Chinese and Southeast Asians.
2. Cause is unknown, although disordered immune regulation is probably involved.
3. Lung and usually hilar lymph nodes are involved in 90% of cases.
4. Other organs with symptomatic involvement include spleen, liver, bone marrow, eye, skin, and brain.
5. Typical histologic feature in lung – non-necrotizing granulomas distributed along lymphatic routes, often accompanied by dense fibrosis.
6. Marked predominance of CD4+ helper T cells in lesions, which is reflected in bronchoalveolar lavage fluid.

Question 24

Hypersensitivity Pneumonitis

Answer 24

Hypersensitivity pneumonitis (HP) is the term used for a group of related acute to chronic interstitial lung diseases, caused by heightened sensitivity and an inappropriate inflammatory reaction to inhaled organic antigens. Specific diseases are named after their etiologies (e.g., bird-fancier’s lung from exposure to avian protein antigens). Initial lesions lack mature fibrosis and are reversible, but mature fibrosis with a pathologic UIP pattern can occur with repeated attacks.

Question 25

Common Forms of HP

Answer 25

1. “Farmer’s lung”: Spores of thermophilic bacteria in newly harvested hay. 2. “Pigeon breeder’s lung”: Proteins from serum, droppings, or bird feathers. 3. “Humidifier lung”: Thermophilic bacteria in heated water reservoirs.

Question 26

Clinical Features of HP

Answer 26

1. Symptoms related to exposure to antigens. 2. Fever, dyspnea, cough, and leukocytosis. 3. Pulmonary infiltrates.

Question 27

Pathologic Features of HP

Answer 27

1. Lymphoplasmacytic interstitial infiltrate in lungs. 2. Small non-necrotizing granulomas around airways. 3. Chronic bronchiolitis. 4. In chronic HP where fibrosis ensues, a UIP pattern of fibrosis can be observed.

Question 28

Desquamative Interstitial Pneumonia

Answer 28

Desquamative interstitial pneumonia (DIP) is a smokingrelated interstitial lung disease, characterized by accumulation of huge numbers of macrophages within alveolar spaces, often accompanied by mild interstitial fibrosis.

Question 29

Characteristics of DIP

Answer 29

1. Virtually always associated with smoking. 2. Symptoms include chronic dyspnea, dry cough, and clubbing of digits. 3. Treatment requires smoking cessation, often with steroid treatment. 4. Prognosis is usually good, but occasional patients progress and develop worse fibrosis.

Question 30

Respiratory Bronchiolitis Associated Interstitial Lung Disease

Answer 30

Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) is another smoking-related interstitial lung disease, closely related to DIP but generally milder, characterized by accumulation of lesser numbers of macrophages within alveolar spaces (compared to DIP), with mild peribronchiolar fibrosis.

Question 31

Characteristics of RB-ILD

Answer 31

1. Virtually always associated with smoking. 2. Symptoms include mild chronic dyspnea and dry cough. 3. Treatment requires smoking cessation. 4. Prognosis is usually good.

Question 32

Pulmonary Alveolar Proteinosis

Answer 32

Pulmonary alveolar proteinosis (PAP) is a rare disease caused by accumulation of surfactant within alveolar spaces because of lack of granulocyte- macrophage-colony-stimulating factor (GM-CSF).

Question 33

Characteristics of PAP

Answer 33

1. Three types: a. Autoimmune PAP (90% of cases), caused by anti-GM-CSF autoantibodies that neutralize the function of GM-CSF, which impairs differentiation of alveolar macrophages so they cannot catabolize surfactant protein. b. Secondary PAP, caused by other rare conditions that secondarily impair macrophage function. c. Hereditary PAP, caused by mutations that disrupt GM-CSF signaling. 2. Does not lead to chronic fibrosis. 3. One third of patients get better, one third stay the same, and one third get worse. 4. Symptoms include cough with abundant gelatinous sputum and dyspnea. 5. Secondary infections can occur. 6. Treatment is whole-lung lavage to remove accumulated surfactant. 7. In autoimmune PAP, treatment also includes GM-CSF therapy.

Question 34

Answer 34

Question 35

Answer 35

Question 36

Pulmonary Hemorrhage Syndrome

Answer 36

* Idiopathic hemosiderosis * Goodpasture’s (antibasement membrane antibody) syndrome: lung + kidney * Microvasculitis (capillaritis); lupus, Wegener’s (polyangiitis with granulomatosis), hypersensitivity

Question 37

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Question 38

Answer 38

Question 39

Pathologic Diagnosis of Interstitial Disease (after history, labs, imaging, etc. don’t yield an answer)

Answer 39

* Broncho-alveolar lavage * Bronchial/transbronchial lung biopsy * VATS (Video-Assisted Thoracic Surgery) wedge biopsy - Need to biopsy 2 different lobes - Send for microbiologic culture - Sample advancing front of disease