Restrictive lung diseases\

Question 1

What are the two general restrictive lung diseases?

Answer 1

1) Chronic interstitial (infiltrative) diseases

2) Chest wall disorders (NM diseases, severe obesity, pleural disease)

Question 2

What characterizes the chronic interstitial diseases?

Answer 2

1) All of them have inflammation and fibrosis of the interstitium

2) Some of the diseases have intra-alveolar components (occurs when the lumen of the alveoli is affected)

3) Many of those diseases are of an unknown etiology

Question 3

What is the typical presentation of restrictive lung diseases?

Answer 3

1) Restrictive hypoventilation

2) Impaired diffusion

3) Dyspnea (CO2 isn’t accumulated)

4) Hypoxia

5) Cyanosis

6) When examining the patient at the end of inspiration you will hear a belt-like sound with crackles as the air hits the affected wall

7) No wheezing

Question 4

What will you see in a chest radiograph in patients with restrictive lung disease?

Answer 4

1) Bilateral nodules

2) Irregular lines (fibrosis)

Question 5

What are the complications of restrictive lung disease?

Answer 5

1) Secondary Pulmonary Hypertension

2) Right-side heart failure (cor pulmonale)

Question 6

What is meant by the usual interstitial pneumonia (UIP)?

Answer 6

It is the abnormal epithelial repair at sites of chronic injury, increasing the fibroblastic proliferation, with fibroblastic foci, With no intra-alveolar pathology

• It increases the risk of lung cancer

Question 7

What is the etiology of usual interstitial pneumonia?

Answer 7

• It is of unknown cause but,

1) It usually occurs in males that are older than 50 years old

2) Environmental factors like cigarette smoking, metal fumes, and wood dust, that cause recurrent alveolar damage are usually associated with it

3) Genetic factors like the loss of germline function due to the loss of telomeres, or genetic variations that lead to the increase in mucin (MUC5B)

4) Impaired immunity (AID, like rheumatic disease)

Question 8

Describe the morphology of usual interstitial pneumonia

Answer 8

1) Gross:

• Pleura is “COBBLESTONE”
• Cut surface shows white area of fibrosis

2) Microscopic:

• Fibroblastic foci (heterogenous fibrosis):

1) Pathcy and myxoid areas (subpleural and para septal, this indicates that normal tissue is beside an abnormal one”)
2) Early and late fibrotic lesions are found at the same time (“TEMPORAL HETEROGENEITY”)
3) Areas of fibrosis are adjacent to normal-appearing lung parenchyma

• Patchy chronic inflammation
• Architectural distortion and (“HONEYCOMBING”) (the fibrosis will destroy the alveolar architecture, forming cysts lined by hyperplastic type-2 pneumocytes)

Question 9

What is the treatment of the usual interstitial pneumonia?

Answer 9

• Anti-fibrotic therapy

1) Nintedanib

2) Pirfenidone (TGF-B inhibitor)

Question 10

What is meant by non-specific interstitial pneumonia?

Answer 10

• It is the second most common type of interstitial pneumonia
• It is non-specific and thus there is a varying degree of fibrosis and inflammation that does not match the criteria of any of the well-characterized interstitial diseases with a better prognosis
• There is no intra-alveolar pathology

Question 11

What is the morphology of the non-specific interstitial pneumonia?

Answer 11

• There is DIFFUSE & UNIFORMED Fibrosis (TEMPORAL HOMOGENEITY), due to chronic interstitial inflammation

Question 12

What is meant by cryptogenic organizing pneumonia (Bronchiolitis obliterans organizing pneumonia)?

Answer 12

Cryptogenic “Unknown” Organizing “Healing” Pneumonia

• What happens is a factor (fumes, bacteria, viruses, etc.) has injured the alveolar & bronchiolar epithelium and during the repair, you’ll have a fibrous plug in the alveoli. This body comprises fibrous tissue + necrotic cells + inflammatory cells + fibroblasts+ collagen etc.
• Pneumonia is present here, with intra-alveolar component
• It is not specific for any etiological agent, seen in many settings, Inhalation of toxic materials, after administration of some drugs
• Cigarettes are not a predisposing factors

Question 13

Describe the morphology of the cryptogenic organizing pneumonia

Answer 13

1) Radiology

• Atoll sign (characteristic for BOOP, wherein the CT you will find a black area surrounded by a white area “like an island”)

2) Microscopic

• Patchy
• Nodules of myxoid loose tissue with plasma cells, lymphocytes, and histiocytes (Masson bodies “APC”) filling the alveolar spaces and bronchioles “Bronchiolitis obliterans”
• Mild chronic interstitial inflammation with fibrosis

Question 14

What is meant by acute respiratory distress syndrome (ARDS, “Acute Lung Injury ALI”, “Acute Interstitial Pneumonia AIP”, Diffused Alveolar Damage DAD”)?

Answer 14

Respiratory Failure within 1-week of a known clinical insult, with bilateral opacities on the chest imaging that are not fully explained by effusion, atelectasis, cardiac failure, or fluid overload

Question 16

What is the cause of acute respiratory distress syndrome?

Answer 16

• Extensive bilateral injury to the alveoli:

1) Primary pulmonary disease (PNEUMONIA): COVID-19, Aspiration

2) Severe systemic inflammation: Trauma, Sepsis, Pancreatitis, transfusion reaction ( excessive immune response. The immune system will pour many cytokines that reach the lung, activating the endothelium of the pulmonary capillaries, and attracting neutrophils. It releases all the mediators in it damaging everything around it, The macrophages will come and try to clean up and induce fibrosis and this is why this syndrome although “acute” was grouped here due to it ultimately leading to fibrosis)

Question 17

What is the pathogenesis of acute respiratory distress syndrome?

Answer 17

• Endothelial & epithelial injury

1) Endothelial activation

• Caused by pneumocyte injury or circulating inflammatory mediators, resulting in the binding of the neutrophils to the activated- end emigrating to the alveoli and interstitium releasing mediators, ROS, and proteases

2) Accumulation of intra-alveolar fluid and formation of HYALINE MEMBRANE (due to the protein-rich edema)

• Hyaline Membrane 🡪 pinkish appearance in which the membrane has no functional cells
• Endothelial activation and injury make the pulmonary capillaries leaky leading to interstitial and intra-alveolar edema (protein-rich edema, where fluid and debris accumulate), in addition to the damage of the type-2 pneumocytes which will decrease the amount of surfactant produced decreasing gas exchange

3) If inflammation persists

• Fibrosis will occur due to the removal of debris by the macrophages releasing fibrogenic cytokines (TGF-B, PDGF)
• Bronchial stem cell proliferation to replace the damaged pneumocytes

Question 18

What is the clinical presentation of acute respiratory distress syndrome?

Answer 18

1) Abrupt onset of hypoxemia

2) Bilateral pulmonary edema (without cardiac failure)

Question 19

Describe the morphology of the acute respiratory distress syndrome

Answer 19

1) Gross:

• In the acute stage the lungs are dark red, firm, airless, and heavy

2) Microscopic:

• Changes are uniform, bilateral, and patchy
• Hyaline membrane (Fibrin rich edema fluid, with the remnant of necrotic epithelial cells)
• Exudative phase (Necrosis, exudate, & alveolar collapse)
• Fibrotic phase (thick interstitial fibrosis)

Question 20

Which restrictive lung disease can increase the risk of lung cancer?

Answer 20

1) Usual interstitial pneumonia

2) Silicosis (pneumoconiosis)

3) Asbestosis (pneumoconiosis)

Question 21

Which restrictive lung disease occurs due to severe systemic disease?

Answer 21

Respiratory distress syndrome

Question 22

What is meant by pneumoconiosis?

Answer 22

It is a disease of the lung caused by the inhalation of organic and non-organic dust

• Specific types of pneumoconiosis are named according to the dust that causes it

Question 23

What are the different types of pneumoconiosis?

Answer 23

1) Coal worker pneumoconiosis

2) Silicosis

3) Asbestosis

Question 24

Describe the pathogenesis of pneumoconiosis

Answer 24

• Pneumo (AIR) Coniosis (DUST)
• The development of symptomatic pneumoconiosis depends on genetics, amount, size-shape-solubility (particles of 1-5micrometer are the most dangerous), and the ability to fibrose
• Macrophages will accumulate, engulfing the trapped particles, and releasing inflammasome and mediators, which will ultimately lead to fibrosis and collagen formation
• Coal doesn’t stimulate fibrosis, while silica, asbestos, and beryllium do
• Cigarettes will act as a surface for the chemical to absorb on

Question 25

What is coal worker pneumoconiosis, and what are its different types?

Answer 25

• It is a pneumoconiosis caused by the inhalation of coal particles (Anthracite “hard coal” more than Bituminous “soft” coal)

1) Asymptomatic anthracosis:

• Inhaled coal pigment in the alveolar and interstitial macrophages

2) Simple coal worker pneumoconiosis:

• Coal macules (carbon-laden macrophages, in the respiratory bronchioles)
• Coal nodules (Macules + fibrosis, found in the upper zones near the resp bronchioles)

3) Complicated coal worker pneumoconiosis (progressive massive fibrosis):

• After several years
• Blacked scars
• Central necrosis
• Dense fibrosis

Question 26

What is meant by silicosis?

Answer 26

• It is a cause of pneumoconiosis due to the inhalation of silicon dioxide, crystalline silica being more fibrogenic (usually in sandblasting and hard-rock mining workers)

Question 27

Describe the pathogenesis of silicosis

Answer 27

1) Silicon particles get ingested by the macrophages releasing inflammasome

2) Silica is toxic to macrophages inducing their death and release causing more fibrosis and once ingested by other macrophages the process will repeat

3) Tubersclerosis + Increased risk of lung cancer

Question 28

Describe the morphology of silicosis

Answer 28

• Simple nodular silicosis in the upper zones
• Hilar lymph nodes with eggshell calcification at the periphery
• The silicotic nodule has collagen in the center, macrophages, lymphocytes & fibroblasts at the periphery
• You need a polarized light microscope to see the silica

Question 29

What is meant by asbestosis?

Answer 29

• It is a cause of pneumoconiosis
• Asbestosis is a hydrated magnesium silicate material that separates into fibers when crushed it can either be serpentine (white asbestosis) or amphiboles (more toxic)
• They affect the distal lung, close to the mesothelial layer, they then get ingested by the macrophages promoting the release of inflammasome
• Asbestos acts as a tumor initiator and promoter, increasing the risk of lung cancer both in the workers and their families

Question 30

Describe the lesion of asbestosis

Answer 30

1) Diffused pulmonary interstitial fibrosis

• The fibrosis appears as a honeycomb
• The asbestos bodies (ferruginous bodies) are coated with a film of protein which is rich in iron (appears as golden brown)

2) Localized fibrous pleural plaques

• Bilateral white plaques, in the anterior and posterior aspect of the parietal pleura and over the dome of the diaphragm
• Dense fibrous tissue without asbestos bodies

3) Diffuse fibrosis in the pleura (after 10 years)

4) Pleural effusion

5) Malignant tumors (after 15 years)

• Malignant pleural and peritoneal mesothelioma
• Lung carcinoma
• Laryngeal carcinoma

Question 31

Which pneumoconiosis affects the upper lobe?

Answer 31

1) Coal

2) Silica

• Asbestosis affects the lower lobes

Question 32

What are the different types of lung granulomatous diseases?

Answer 32

• Granuloma is a nodule collection of chronic inflammatory cells (lymphocytes, plasma & macrophages)

1) Sarcoidosis

2) Hypersensitivity Pneumonitis

Question 33

What is sarcoidosis?

Answer 33

• It is a chronic multi-system granulomatous disease of unknown etiology, with lung symptoms and bilateral hilar lymph nodes
• It is more common in young females and non-smokers

Question 34

What are the risk factors for sarcoidosis?

Answer 34

1) Environmental factors:

• Infections
• Danish & Swedish ppl + African ppl of the US

2) Genetic predisposition

• Specific HLA genotype

3) Immunologic dysregulation

• Intra-alveolar and interstitial accumulation of CD4 cells, resulting in a CD4/CD8 5:1 dysregulation
• Peripheral T-cell cytopenia
• Increased levels of mediators (cytokines)
• Impaired dendritic function

Question 35

Describe the morphology of sarcoidosis

Answer 35

1) Gross

• Nodules in the bronchial mucosa
• Skin (erythema)
• Eye and lacrimal ducts (iritis, glaucoma)
• Parotid gland (Xerostomia “dry mouth”
• Spleen & liver (granuloma)

2) Microscopically

• Granuloma (small non-caseating)

SOHA (females + 4 microscopic findings)

• MNG BODIES: (Shuman “laminated concretions composed of Ca2+), Asteroid Bodies (stellate inclusion of Ca), Hamazaki-wesenberg (golden brown pigment), Calcium Oxalate crystals
• Hypercalcemia is due to the deposition of active vitamin D from the MNG BODIES increasing blood calcium in the blood and urine

Question 36

What is meant by hypersensitivity pneumonitis (extrinsic allergic alveolitis)?

Answer 36

-Type 3 & 4 hypersensitivity rxn

• It is a bilateral interstitial granulomatous lung disease that occurs in the upper lobe due to an abnormal sensitivity to inhaled organic agents (Fungi, bacteria, chemicals, birds, etc) with intense & prolonged exposure
• The organic dust will increase the levels of inflammation, chemokines, T-cells, serum antigen against the causative agent
• Non-caseating granuloma

Question 37

What are the different syndromes of hypersensitivity pneumonitis?

Answer 37

1) Bagassosis

2) Farmer’s lung

3) Pigeon breeder’s lung

4) Humidifier/air conditioner lung

Question 38

Describe the morphology of Hypersensitivity pneumonitis

Answer 38

• Found around bronchioles

1) Non-fibrotic triad:

• Patchy interstitial inflammation with chronic inflammatory cells
• Bronchiolitis
• Non-caseating granulomas

2) Fibrotic, interstitial fibrosis of the upper-lobe dominant

Question 39

What is interstitial pneumonia and its types?

Answer 39

• Smoking-related ILD

1) Desquamative Interstitial Pneumonia (DIP)
- sLOUGHING OF EPITHELIAL CELLS, where pigmented macrophages with distal airspace are found

2) Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD)

• Pigmented macrophages around the bronchioles with chronic inflammation and peribronchial fibrosis

3) Pulmonary Langerhans cells histiocytosis (accumulation and proliferation of immune cells)

• In the lungs, it is a reactive process due to smoking, in all other organs it is considered cancer
• Found in young to middle-age
• It is an abnormal immune response to cigarette smoke
• Usually occurs in the upper lobe, with nodular infiltrate
• Microscopically you can see stellate nodules with Langerhans cells and immune cells + interstitial fibrosis

Question 40

Which restrictive diseases affect the upper lobe?

Answer 40

1) Silicosis

2) Coal worker pneumonia

3) Hypersensitivity pneumonitis

4) Pulmonary Langerhans cell histiocytosis

Question 41

Which restrictive diseases affect the lower lobe?

Answer 41

1) Asbestosis

Question 42

Which restrictive lung disease, is smoking not considered as a risk factor?

Answer 42

1) Cryptogenic organizing pneumonia

2) Sarcoidosis

Question 43

Which diseases occur only in smoking?

Answer 43

1) DIP (Desquamative interstitial pneumonia)

2) RB-ILD (Respiratory bronchiolitis-associated interstitial lung disease)

3) Pulmonary LCH (Langerhans cell histiocytosis)

Question 44

Which restrictive lung disease has a hilar lymph node?

Answer 44

1) Silicosis

2) Sarcoidosis

Question 45

Which lung diseases are of hypersensitivity?

Answer 45

1) Asthma (Type-1 hypersensitivity)

2) Hypersensitivity pneumonitis (Type-3 & 4)

3) Sarcoidosis (Type-4)

Question 46

Which lung diseases contain CD4/CD8?

Answer 46

1) Emphysema (contains both)

2) Chronic bronchitis (CD8)

3) Sarcoidosis (CD4)

4) Hypersensitivity pneumonitis (BOTH)