The Respiratory System

LUNGS – NORMAL STRUCTURE

Anatomy

Right lung: 375–550 g (avg. 450 g), 3 lobes (upper, middle, lower), 2 fissures.
Left lung: 325–450 g (avg. 400 g), 2 lobes (upper, lower), 1 fissure. Middle lobe represented by lingula.
Airway pathway:
Trachea → Right/Left Main Bronchi → Segmental bronchi → Terminal bronchioles → Acinus (functional unit).
Acinus structure:
1. Respiratory bronchioles (3–5 generations)
2. Alveolar ducts
3. Alveolar sacs (alveoli)
Pulmonary lobule: Cluster of 5 acini.

Airway Wall Composition

Trachea/bronchi: Cartilage, smooth muscle, mucous glands.
Bronchioles: Smooth muscle only; no cartilage/mucous glands.

Blood Supply

Dual supply:
- Pulmonary arteries: Deoxygenated blood.
- Bronchial arteries: Oxygenated blood.
Lymphatics: Subpleural plexus → Hilar/tracheobronchial nodes → Thoracic duct.

🧬 Histology

Bronchi/Bronchioles: Lined by pseudostratified ciliated columnar epithelium with goblet cells (decrease toward bronchioles).
Bronchioles: No goblet cells; have Clara cells (secrete lysozyme, Ig; no surfactant).
Alveolar wall (septum):
1. Capillary endothelium
2. Basement membrane + scant interstitium
3. Alveolar epithelium:
  - Type I pneumocytes: 95%, gas exchange.
  - Type II pneumocytes: Microvilli, secrete surfactant, proliferate to replace Type I.
4. Alveolar macrophages
5. Pores of Kohn: Allow inter-alveolar communication (bacteria/exudate spread).

💨 Functions

Gas exchange (O₂ in, CO₂ out)
Clearance of inhaled pollutants via mucociliary action, macrophages, lymphatics
Pulmonary circulation affects and is affected by heart diseases.

PAEDIATRIC LUNG DISEASE

1. Congenital Cysts

Defects in bronchial cartilage, elastic tissue/muscle → cysts.
Large cyst = Pneumatocele
Multiple small cysts = Sponge-like lung appearance.
May rupture → pneumothorax or haemoptysis

2. Bronchopulmonary Sequestration

Lung tissue not connected to airways.
Blood supply: From aorta, not pulmonary arteries.
Types:
- Intralobar: Within pleura.
- Extralobar: Outside pleura, usually in infants, often with anomalies.

ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS)

Also called Hyaline Membrane Disease (HMD)

Types

Neonatal ARDS
Adult ARDS (a.k.a. DAD – Diffuse Alveolar Damage)

🌬️ Clinical Features

Neonatal ARDS: Dyspnoea, cyanosis, rapid breathing post-birth; often fatal.
Adult ARDS: Sudden respiratory failure, cyanosis, stiff lungs, poor response to oxygen.

⚠️ Etiology

Neonatal ARDS:

Prematurity
Diabetic mothers
Caesarean delivery
Male > female
Birth asphyxia
Sedation
Idiopathic

Adult ARDS:

Shock (trauma, sepsis, burns)
Viral infections
Pancreatitis
Toxins, narcotics, radiation
Aspiration, fat embolism
Drugs (salicylates, colchicine)

🔬 Pathogenesis

Neonatal:

↓ Surfactant (from Type II cells) → ↑ surface tension → Atelectasis
Leads to: ↓ ventilation/perfusion → Ischemia → Hyaline membrane formation

Adult:

Cytokine imbalance:
- Pro-inflammatory: IL-1, IL-8, TNF
- Neutrophils → Proteases, oxidants → Tissue damage
Repair phase: Fibrogenic cytokines (TGF-α, PDGF) → Fibrosis
End result: Alveolar/capillary injury → Oedema, hyaline membranes, stiff lungs

🧪 Morphology

Gross:

Lungs: Heavy, airless, sink in water

Microscopy:

Collapsed + dilated alveoli
Necrotic epithelium, eosinophilic hyaline membranes (fibrin + debris)
Oedema, congestion, intra-alveolar haemorrhage
May develop bronchopneumonia
Type II pneumocyte proliferation
Organising stage: Interstitial fibrosis

🧭 Consequences

Death: High neonatal mortality (esp. <1kg); adult ARDS has poor prognosis
Resolution: Possible with supportive care/ventilation
Long-term sequelae:
- Bronchopulmonary dysplasia (in neonates)
- Desquamative interstitial pneumonia (DIP)
- Fibrosing alveolitis (Hamman-Rich syndrome)

2. Bronchopulmonary Dysplasia (BPD)

Occurs in: Neonates treated for ARDS with oxygen + ventilation.
Cause: Oxygen toxicity + barotrauma.
Clinical: Persistent respiratory distress (3–6 months).
Microscopy:
- Fibrous thickening of alveolar walls.
- Bronchiolitis, peribronchial fibrosis, emphysema.
- Squamous metaplasia in bronchioles.

3. Atelectasis & Pulmonary Collapse

Atelectasis:

Primary: Incomplete lung expansion in neonates (esp. stillborn).
Causes: Prematurity, birth injury, CNS defects, intrauterine hypoxia.
Lungs: Small, dark blue, non-crepitant.
Microscopy: Collapsed alveoli, proteinaceous fluid, epithelial squames, possible emphysema/pneumothorax.

Collapse (Secondary Atelectasis):

Occurs in: Previously expanded lungs.
Types:
1. Compressive: Due to external pressure (e.g., pleural effusion, tumour).
2. Obstructive/Absorptive: Airway block (e.g., mucus plug, tumour, foreign body).
3. Contraction: Lung fibrosis leading to collapse.

4. Bronchiolitis & Bronchiolitis Obliterans

Age group: Older children & elderly.
Causes:
- Viral (RSV, adenovirus), bacterial, fungal.
- Inhalation (toxic gases), aspiration.
Microscopy:
- Fibrous plugs in bronchioles.
- Lymphoplasmacytic infiltration.
- Interstitial pneumonitis & alveolar fibrosis.

5. Sudden Infant Death Syndrome (SIDS)

Also called: Crib death.
Age group: 2–6 months.
Risk factors: Prematurity, maternal smoking, drug abuse.
Autopsy: Petechial haemorrhages in lungs & airways.

6. Pulmonary Vascular Disease

Pulmonary Hypertension (PH)

Definition: Pulmonary arterial systolic BP >30 mmHg.
Types:
- Primary (Idiopathic): Rare, mostly young females or children.
- Secondary: More common, typically >50 years.

Primary Pulmonary Hypertension – Possible Causes:

Chronic vasoconstriction.
Thromboemboli/amniotic fluid embolism in pregnancy.
Autoimmune (SLE, scleroderma, RA).
Pulmonary veno-occlusive disease.
Toxins (bush tea, contraceptives, aminorex).
Genetic (familial cases).

Secondary Pulmonary Hypertension – Categories:

A. Passive (↑ pulmonary venous pressure):

Mitral stenosis, LV failure.

B. Hyperkinetic (↑ volume/pressure):

PDA, septal defects.

C. Vaso-occlusive (↓ vascular bed):

Obstructive: Emboli, sickle cell, schistosomiasis.
Obliterative: Emphysema, TB, bronchiectasis, pneumoconiosis.
Vasoconstrictive: High altitude, obesity, neuromuscular disease.

Morphology:

Heart: Right ventricular hypertrophy, right atrial dilation (cor pulmonale).
Vascular changes (affecting all arterial sizes):
- Small arteries/arterioles: Medial hypertrophy, plexiform lesions.
- Medium arteries: Intimal thickening, adventitial fibrosis.
- Large arteries: Atherosclerosis.

PNEUMONIA – DEFINITION

Pneumonia is acute inflammation of the lung parenchyma distal to the terminal bronchioles (includes alveolar ducts, sacs, and alveoli).
Pneumonitis is another term used synonymously.
Consolidation: Solidification of lung tissue, seen grossly or radiologically in pneumonia.

PATHOGENESIS

Microorganisms enter the lungs through:

Inhalation from the air.
Aspiration from oropharynx/nasopharynx.
Haematogenous spread (bloodstream).
Direct spread from adjacent infection.

DEFENSE MECHANISMS OF LUNGS

Nasopharyngeal filtering
Mucociliary clearance
Alveolar macrophages
Immunoglobulins

PREDISPOSING FACTORS

Altered consciousness (e.g. coma, trauma, seizures, alcoholism).
Depressed cough reflex (e.g. post-surgery, neuromuscular disease).
Impaired mucociliary transport (e.g. smoking, viral infections).
Alveolar macrophage dysfunction (e.g. hypoxia, malnutrition).
Endobronchial obstruction (e.g. tumor, foreign body).
Leucocyte dysfunctions (e.g. AIDS, chemotherapy).

CLASSIFICATION OF PNEUMONIAS

Based on Anatomic Involvement

Lobar Pneumonia
Bronchopneumonia (Lobular pneumonia)
Interstitial Pneumonia

Etiologic Classification (Table 17.1)

A. Bacterial Pneumonias

Lobar pneumonia
Bronchopneumonia

B. Viral and Mycoplasmal Pneumonias

Primary atypical pneumonia

C. Other Types

Pneumocystis pneumonia
Legionella (Legionnaire’s disease)
Aspiration pneumonia
Hypostatic pneumonia
Lipid pneumonia

A. BACTERIAL PNEUMONIA

1. LOBAR PNEUMONIA

Definition: Acute bacterial infection affecting part/whole of one or more lobes.

Common Pathogens:

Streptococcus pneumoniae (90% of cases)
Staphylococcus aureus
β-hemolytic streptococci
Klebsiella pneumoniae, Haemophilus influenzae, E. coli, Pseudomonas

Stages of Lobar Pneumonia (Laennec’s Stages)

1. Congestion (1–2 days)

Gross: Dark red, heavy, blood-stained frothy fluid
Microscopy: Dilated capillaries, oedema, few neutrophils, bacteria

2. Red Hepatisation (2–4 days)

Gross: Liver-like red, firm, airless lung
Microscopy: Fibrin, many neutrophils, red cells, engulfed bacteria

3. Grey Hepatisation (4–8 days)

Gross: Grey, firm, granular, dry cut surface
Microscopy: More fibrin, fewer neutrophils/RBCs, macrophages begin to appear

4. Resolution (after day 8–9 or early with antibiotics)

Gross: Frothy, grey-red fluid, softening from center
Microscopy: Macrophages predominant, removal of exudate, lung aeration restored

Complications of Lobar Pneumonia

Organization → Fibrous lung (carnification)
Pleural effusion → May resolve or form adhesions
Empyema → Pus in pleural cavity
Lung abscess
Metastatic infection → Pericarditis, endocarditis, meningitis, brain abscess

Clinical Features

Sudden onset, chills, fever, pleuritic chest pain
Productive cough (mucoid/purulent/bloody)
Neutrophilic leucocytosis
X-ray: Lobar consolidation
Sputum culture guides treatment
Good response to antibiotics (within 48–72 hours)

2. BRONCHOPNEUMONIA (Lobular Pneumonia)

Definition: Patchy bacterial infection around terminal bronchioles and alveoli

Common in:

Infants & elderly
Post-viral infections (e.g. influenza, measles)
Bedridden, debilitated patients

Causative Organisms:

Staphylococci, Streptococci, Pneumococci
Klebsiella pneumoniae, Haemophilus influenzae, Pseudomonas

Morphology:

Gross: Patchy red/grey dry lesions (3–4 cm), lower zones, bilateral
Microscopy:
- Acute bronchiolitis
- Neutrophil-rich exudate in alveoli
- Septal thickening, oedema in less affected areas

Complications:

Bronchiolar fibrosis → Bronchiectasis
Other complications similar to lobar pneumonia

Clinical Features:

History of prior illness or infection
Starts as bronchitis, progresses to pneumonia
Blood: Neutrophilic leucocytosis
X-ray: Patchy, mottled opacities in lower zones

Comparison Table – Lobar vs Bronchopneumonia

Feature	Lobar Pneumonia	Bronchopneumonia
Definition	Involves entire or part of lobe	Patchy infection of bronchioles & alveoli
Age	Adults	Infants & elderly
Predisposing factors	Healthy individuals	Chronic illness, viral infections
Common organisms	Pneumococcus, Klebsiella	Staph, Strep, H. influenzae
Pathology	4 classic stages	Patchy consolidation
X-ray	Consolidation	Mottled opacities
Prognosis	Good	Variable, complications more likely
Complications	Less common	Bronchiectasis, others

B. VIRAL & MYCOPLASMAL PNEUMONIA (Primary Atypical Pneumonia)

Definition: Inflammation confined to interstitial tissue of lungs. No alveolar exudate.

Etiology:

RSV (common)
Mycoplasma pneumoniae
Influenza, adenovirus, rhinovirus, CMV, coxsackievirus
Psittacosis (Chlamydia), Q fever (Coxiella)

Morphologic Features

Gross:

Lungs: Heavy, congested, with patchy to diffuse consolidation
Frothy/bloody fluid on cut surface
Mild or absent pleural reaction

Microscopy:

Interstitial inflammation: Thickened alveolar walls with mononuclear cells (lymphocytes, macrophages, plasma cells)
Necrotising bronchiolitis
Reactive hyperplasia: Multinucleate giant cells, syncytia, viral inclusions (esp. CMV)
Alveolar changes: Oedema, fibrin, hyaline membrane (if severe or bacterial superinfection)

Complications

Superimposed bacterial infection
Severe cases: Interstitial fibrosis

Clinical Features

Starts with upper respiratory symptoms (cold, fever, headache, muscle aches)
Then dry, hacking cough with retrosternal burning
Blood: Neutrophilic leucocytosis
X-ray: Patchy/diffuse consolidation
Cold agglutinin titers ↑ in Mycoplasma and adenovirus
Difficult to isolate organism

C. Other Types of Pneumonias

This category includes infective pneumonias like Pneumocystis carinii and Legionella pneumonia, as well as non-infective types such as aspiration, hypostatic, and lipid pneumonia.

1. Pneumocystis carinii Pneumonia (PCP)

Cause: Pneumocystis carinii (now P. jirovecii) – a protozoan found widely in the environment.
Mode of transmission: Inhalation (opportunistic infection).
Affected groups:
- Neonates
- Immunosuppressed individuals (e.g. HIV/AIDS, chemotherapy, organ transplant, malnutrition, agammaglobulinemia).
- Commonest infection in HIV/AIDS patients.

Morphologic Features:

Gross: Lungs are consolidated, dry, and gray.
Microscopy:
1. Interstitial pneumonitis with mononuclear infiltrate in alveolar walls.
2. Alveoli filled with pink frothy fluid containing organisms.
3. GMS stain reveals:
  - Oval or crescentic cysts (~5 μm)
  - Tiny black dot-like trophozoites.
4. No significant inflammatory exudate.

Clinical Features:

Rapid onset dyspnoea, tachycardia, cyanosis, non-productive cough.
Fatal in 1–2 weeks if untreated.
Chest X-ray: Diffuse alveolar and interstitial infiltrates.

2. Legionella Pneumonia (Legionnaire’s Disease)

Cause: Legionella pneumophila – Gram-negative bacillus.
Source: Contaminated water (e.g., cooling towers, drinking water).
Predisposing Factors: Immunodeficiency, corticosteroids, old age, smoking.

Morphologic Features:

Gross: Widespread bronchopneumonia, pleural effusion common.
Microscopy:
1. Intra-alveolar exudate – early neutrophils, later macrophages.
2. Septal epithelial hyperplasia and thrombosis.
3. Organisms seen in macrophages (special stains, immunofluorescence).

Clinical Features:

Malaise, headache, myalgia → fever, chills, cough, tachypnea.
Bacteremia may lead to:
- Abdominal pain, diarrhea, proteinuria, mild liver dysfunction.

3. Aspiration (Inhalation) Pneumonia

Cause: Inhalation of food, gastric contents, oropharyngeal material.
Risk Factors: Unconsciousness, intoxication, neurological disorders, tumors, infants, tracheoesophageal fistula.

Morphologic Types:

Sterile Aspirate (e.g., gastric acid):
- Chemical pneumonitis
- Hemorrhagic edema, particles in bronchioles
- Cyanosis, shock, bloody sputum
Non-Sterile Aspirate:
- Bronchopneumonia with necrosis and suppuration
- Granulomas with foreign body giant cells

4. Hypostatic Pneumonia

Cause: Stagnation of fluid in basal/posterior lung parts in debilitated patients.
Common in: Bedridden, comatose, or elderly patients.
Mechanism: Accumulated fluid gets infected by URT flora → pneumonia.

5. Lipid Pneumonia

Two Types:
1. Exogenous: Aspiration of oily materials (nasal drops, paraffin, oily vitamins).
2. Endogenous: Tissue breakdown due to obstruction (cancer, TB, bronchiectasis).

Morphologic Features:

Gross: Right lung often affected; golden-yellow consolidated areas.
Microscopy:
- Foamy macrophages in alveoli (lipid-filled)
- Cholesterol clefts, granulomas with foreign body giant cells

Lung Abscess

Definition: Localized necrosis with suppuration of lung tissue.

Types:

Primary: In normal lung; mostly due to aspiration.
Secondary: Complication of other lung diseases or systemic infections.

Etiology:

Organisms: Streptococci, staphylococci, Gram-negative bacteria.
Sources:
- Aspiration (infected material, food, necrotic tissue)
- Preceding infections (e.g., TB, bronchiectasis)
- Bronchial obstruction (tumor, foreign body)
- Septic embolism
- Others: infarcts, amoebiasis, trauma, direct spread

Morphologic Features:

Site: Right lung, lower part of upper lobe or apex of lower lobe.
Gross:
- Single (primary) or multiple (secondary) cavities (mm to 5–6 cm)
- Acute: ragged wall; Chronic: fibrous wall
Microscopy:
- Suppurative exudate
- Chronic inflammatory infiltrate
- Fibrocollagenous wall in chronic abscess

Clinical Features:

Fever, malaise, weight loss, purulent sputum, hemoptysis
Clubbing (20%), secondary amyloidosis in chronic cases

Fungal Infections of Lung

More common than TB in the US; serious in immunocompromised.

1. Aspergillosis

Cause: Aspergillus fumigatus
Forms: Allergic bronchopulmonary aspergillosis, aspergilloma, necrotizing bronchitis
High risk: Leukemia, HIV/AIDS
Gross: Fungal ball in preexisting cavities
Microscopy:
- Septate hyphae with acute angle branching
- PAS and silver stain positive
- Chronic inflammation in cavity wall

2. Mucormycosis

Cause: Mucor, Rhizopus
Seen in: Diabetic ketoacidosis
Features:
- Broad, non-septate hyphae with obtuse branching
- More destructive than aspergillosis

3. Candidiasis

Cause: Candida albicans
Commensal → pathogenic in immunosuppression
May invade blood vessels (angioinvasion)

4. Histoplasmosis

Cause: Histoplasma capsulatum (inhalation of bird droppings)
Lesions: Ghon’s complex-like

5. Cryptococcosis

Cause: Cryptococcus neoformans (pigeon droppings)
Lesions: Granuloma in lung, may cause meningitis

6. Coccidioidomycosis

Cause: Coccidioides immitis (contact with infected dogs)
Lesions: Peripheral granulomas

7. Blastomycosis

Cause: Blastomyces dermatitidis (inhaled spores)
Lesions: Ghon-like, pneumonia, skin nodules

📌 Fungal Pneumonias

1. Cryptococcosis

Cause: Cryptococcus neoformans (round yeast with a halo in tissues).
Source: Inhalation of pigeon droppings.
Lesions: Range from lung granuloma to cryptococcal meningitis.

2. Coccidioidomycosis

Cause: Coccidioides immitis (spherical spores).
Source: Close contact with infected dogs.
Lesion: Peripheral granuloma in the lung parenchyma.

3. Blastomycosis

Cause: Blastomyces dermatitidis.
Source: Inhalation of spores from soil.
Lesions:
- Ghon’s complex-like lesion
- Pneumonic consolidation
- Multiple skin nodules

Pulmonary Tuberculosis (TB)

Type of Inflammation: Chronic Granulomatous Inflammation

1. Causative Agent

Mycobacterium tuberculosis (Koch’s bacillus)
Strict aerobe; thrives in oxygen-rich tissues (e.g., lung apex)
Human strains: M. tuberculosis hominis, M. bovis (rare), M. africanum, etc.

2. Morphology of Granuloma (Tubercle)

A fully-developed tubercle is ~1 mm in diameter and shows:

Central caseation necrosis (cheese-like)
Surrounding epithelioid cells
Langhans’ giant cells (20+ nuclei arranged peripherally)
Peripheral lymphocytes
Encapsulating fibroblasts and fibrosis

3. Cellular Components of TB Granuloma

Epithelioid cells: Modified macrophages; pale eosinophilic cytoplasm; weakly phagocytic.
Multinucleated giant cells: From fusion of epithelioid cells.
- Langhans’ type (TB): nuclei in horseshoe/ring.
- Foreign body type: central nuclei.
Lymphocytes: Cell-mediated immunity
Plasma cells: Humoral response
Necrosis: Central caseation
Fibrosis: Healing response

4. Diagnostic Methods

Ziehl-Neelsen stain: Acid-fast bacilli (AFB)
Culture: Lowenstein-Jensen medium (6 weeks)
PCR: Rapid, sensitive
Fluorescent stains
Guinea pig inoculation (historical)

5. Hypersensitivity & Immunity

Type IV hypersensitivity (cell-mediated)
Immune response due to cord factor & Wax-D
Tuberculin (Mantoux) test: PPD injection → ≥15mm induration in 72 hrs indicates previous exposure
Koch’s phenomenon: Demonstrates immune memory in reinfection

6. Evolution of Tubercle (Granuloma)

Neutrophils arrive but fail
Macrophages dominate
T/B cells activated → CD4+ cells induce granuloma formation
Epithelioid cells form, fuse into giant cells
Lymphocytes + fibroblasts surround
Caseation necrosis appears (7–14 days)
Possible fate:
- Liquefaction → cold abscess
- Sinus formation
- Coalescence → fibrosis
- Calcification or ossification

7. Types of Tuberculosis

A. Primary Tuberculosis (Ghon’s Complex)

Occurs in non-sensitized individuals
Common in children
Three components:
1. Ghon’s focus: Subpleural lesion (lung)
2. Draining lymphatics: Show tubercles
3. Hilar lymphadenopathy: Caseation
Fate:
- Healing → fibrosis/calcification
- Progression → active spread or miliary TB
- Reactivation → secondary TB

B. Secondary Tuberculosis (Reactivation or Reinfection)

In previously sensitized individuals
Often in lung apex (high O₂)
Lesions: Caseating granulomas with peripheral fibrosis
Can arise from:
- Reactivation of dormant focus
- Fresh exogenous infection

8. Spread of Tuberculosis

Local: Macrophage migration
Lymphatic: Regional lymph nodes
Haematogenous: Miliary TB (liver, spleen, kidney, brain)
Natural passages:
- Pleura → pleurisy
- Larynx → laryngitis
- GI tract → ileocaecal TB
- Kidney → bladder

9. Atypical Mycobacteria (Non-Tuberculous Mycobacteria)

Environmental mycobacteria; acid-fast
Include: M. avium, M. kansasii, M. fortuitum, M. ulcerans
Less virulent, not spread person-to-person
Classified as:
- Rapid growers: M. fortuitum, M. chelonae
- Slow growers:
  - Photochromogens: Pigment in light
  - Scotochromogens: Pigment in light/dark
  - Non-chromogens: No pigment

10. HIV-Associated Tuberculosis

High incidence in HIV/AIDS patients
Presents with sputum smear-negative but culture-positive TB
More extrapulmonary involvement: Lymph nodes, pleura, meninges
Also prone to M. avium-intracellulare infection

11. Key Examples of Granulomatous Inflammation

Condition	Agent	Feature
TB	M. tuberculosis	Caseating granuloma
Leprosy	M. leprae	Foamy histiocytes, granulomas
Sarcoidosis	Unknown	Non-caseating granulomas
Fungal infections	Cryptococcus, Blastomyces	Granulomas with yeast/fungi
Foreign body	Talc, suture	Foreign body granulomas

📌 Chronic Obstructive Pulmonary Disease (COPD)

➤ Definition:

Group of chronic lung diseases with obstructed airflow at various levels, resulting in lung function disability.

➤ Major Types:

Chronic bronchitis
Emphysema
Bronchial asthma
Bronchiectasis

📌 Chronic Bronchitis

➤ Definition:

Persistent cough with expectoration for ≥ 3 months/year for 2 consecutive years.

➤ Etiopathogenesis:

Smoking (most common):
- ↓ Ciliary activity
- ↓ Alveolar macrophage function
- ↑ Mucus glands (hypertrophy, hyperplasia)
- ↑ Bronchial obstruction & bronchoconstriction
Air Pollution: Sulfur dioxide, nitrogen dioxide, dust, fumes.
Occupation: Exposure to dust in cotton mills, plastics.
Infection: Secondary bacterial or viral infections.
Genetics/Familial Factors: May contribute, especially via passive smoking.

➤ Morphologic Features:

Gross: Thickened, oedematous bronchial walls with mucus plugs.
Microscopic:
- ↑ Reid Index (submucosal gland thickness to total wall)
- Squamous metaplasia, goblet cell hyperplasia
- Mucus plugging, mild chronic inflammation

➤ Clinical Features:

Persistent productive cough
Recurrent infections
Dyspnoea on exertion
"Blue Bloaters": Cyanosis, edema, right heart failure (cor pulmonale)
CXR: Enlarged heart, prominent vessels

📌 Emphysema

➤ Definition (WHO):

Permanent dilatation of distal airspaces
Destruction of alveolar walls
Clinically and pathologically distinct from chronic bronchitis

➤ Types (True Emphysema):

Centriacinar (Centrilobular)
Panacinar (Panlobular)
Paraseptal (Distal Acinar)
Irregular (Para-cicatricial)
Mixed (Unclassified)

➤ Overinflation Types:

Compensatory overinflation
Senile hyperinflation
Obstructive overinflation (e.g. infantile lobar)
Unilateral translucent lung
Interstitial (Surgical) emphysema

📌 Etiopathogenesis of Emphysema

➤ Protease-Antiprotease Hypothesis:

α1-antitrypsin (α1-AT) inhibits neutrophil elastase
In α1-AT deficiency (especially PiZZ genotype):
- Loss of elastase inhibition → alveolar destruction
- Associated with emphysema + liver cirrhosis
Smoking contributes by:
- Inactivating α1-AT
- ↑ Neutrophil elastase production

📌 Pathologic Features of Emphysema

➤ Gross:

Overinflated, pale lungs
Rounded edges
Subpleural bullae and blebs

➤ Microscopic:

Dilated airspaces
Destroyed septal walls
Loss of elastic tissue
Inflammatory changes vary by type

📌 Clinical Features of Predominant Emphysema

Long history of progressive dyspnoea
Use of accessory muscles
Barrel-shaped chest
Late-onset cough with scanty sputum
"Pink Puffers": well oxygenated, tachypnoeic
Weight loss common
Late-stage: Cor pulmonale, respiratory failure
CXR: Small heart, hyperinflated lungs

📌 Comparison: Predominant Bronchitis vs. Emphysema

Feature	Predominant Bronchitis	Predominant Emphysema
Age at diagnosis	~50 years	~60 years
Pathology	Mucus gland hypertrophy	Alveolar wall destruction
Dyspnoea	Late, mild	Early, severe
Cough	Early	Late
Sputum	Copious, purulent	Scanty, mucoid
Infections	Frequent	Rare
Cyanosis	Common ("blue bloaters")	Rare ("pink puffers")
Heart failure	Common	Terminal stage
CXR findings	Large heart, prominent vessels	Small heart, hyperinflated lungs

📌 Types of Emphysema: Morphology

Centriacinar:
- Central respiratory bronchioles affected
- Upper lobes
- Associated with smoking, coal workers
Panacinar:
- Whole acinus involved
- Lower lobes
- Associated with α1-AT deficiency
Paraseptal:
- Distal acinus affected
- Subpleural region
- Common cause of spontaneous pneumothorax
Irregular:
- Scarring around healed lesions
- Often asymptomatic
Mixed:
- Combination of above types in elderly smokers

📌 Types of Overinflation

Type	Description	Cause
Compensatory	Enlargement of remaining lung after surgery	Post-lobectomy
Senile	Aging-related lung dilation	Elastic tissue loss
Obstructive	Air trapping due to obstruction	Foreign body, tumor
Unilateral	One-sided translucent lung	Childhood bronchiolitis
Interstitial	Air in lung connective tissue	Alveolar rupture, trauma, surgery

1. Interstitial Emphysema (Surgical Emphysema)

Definition: Entry of air into connective tissue framework of lung.
Causes:
- Violent coughing (e.g., whooping cough, bronchitis)
- Rupture of esophagus or trauma to lung/trachea
- Air entry during surgery
- Fractured ribs puncturing lung
- Sudden pressure changes (e.g., decompression sickness)
Pathology:
- Air leaks from ruptured alveoli to connective tissues → mediastinum, pleura, subcutaneous tissue
- Can lead to pneumothorax
Histology:
- Alveoli distended; septa intact
- Not true emphysema
- Clear air spaces in connective tissue

2. Bronchial Asthma

Definition: Hyperresponsive airways leading to reversible airway narrowing
Symptoms: Dyspnoea, cough, wheezing
Severe form: Status asthmaticus (may be fatal)
Epidemiology:
- ~4% in US
- 50% cases begin before age 10

Types of Asthma

Feature	Extrinsic (Atopic/Allergic)	Intrinsic (Non-atopic)
Age	Childhood	Adult
Allergy History	Present	Absent
Allergens	Present	Absent
Serum IgE	Elevated	Normal
Nasal polyps/Chronic bronchitis	Absent	Present
Drug Sensitivity	Rare	Often (e.g. Aspirin)

Pathogenesis

Extrinsic Asthma:
- IgE-mediated Type I hypersensitivity
- Triggered by allergens (e.g., dust, pollen)
- Acute Phase: Mast cells → histamine, leukotrienes → bronchospasm, edema, mucus
- Late Phase: Eosinophils, neutrophils → prolonged inflammation
Intrinsic Asthma:
- Triggered by infections (esp. viral), cold, stress, drugs (e.g., aspirin)
- No IgE involvement
Mixed Type: Overlapping features

Morphology

Gross: Overinflated lungs, mucus plug occlusion
Microscopy:
1. Curschmann’s spirals: Twisted mucus with epithelium
2. Charcot-Leyden crystals: Eosinophil-derived crystals
3. Thickened basement membrane
4. Submucosal gland & smooth muscle hypertrophy
5. Inflammatory infiltrates (eosinophils, lymphocytes)

Clinical Features

Paroxysms of dyspnoea, wheezing, and cough
Eosinophilia in blood and sputum
Chronic asthma may lead to cor pulmonale

3. Bronchiectasis

Definition: Irreversible dilation of bronchi/bronchioles (>2 mm)
Symptoms: Persistent cough with foul-smelling, purulent sputum, haemoptysis, recurrent pneumonia

Etiology & Pathogenesis

Two major mechanisms:
- Obstruction: Tumors, foreign bodies, lymph node compression
- Infection: Often secondary to obstruction or severe necrotizing pneumonia

Associated Conditions:

Congenital/Hereditary:
- Congenital bronchiectasis
- Cystic fibrosis
- Immotile cilia syndrome (e.g., Kartagener’s syndrome)
Obstructive causes:
- Tumors, foreign body, TB scarring
Secondary to infections:
- Staphylococcal pneumonia, TB

Morphology

Gross:
- Lower lobes commonly affected
- Dilated bronchi reaching pleura; types: cylindrical, fusiform, saccular, varicose
- Honeycomb lung appearance
Microscopy:
- Ulceration or squamous metaplasia of epithelium
- Inflammatory infiltrates
- Destruction of smooth muscle and elastic tissue
- Surrounding lung: fibrosis, interstitial pneumonia

Clinical Features

Chronic cough with copious foul sputum
Haemoptysis, recurrent infections
Complications: Clubbing, brain abscess, amyloidosis, cor pulmonale

4. Chronic Restrictive Pulmonary Disease

Definition: Reduced lung expansion, decreased total lung capacity

Types:

A. Chest Wall Disorders:

Kyphoscoliosis, poliomyelitis, severe obesity, pleural disease

B. Interstitial Lung Diseases (ILDs):

200 types with common clinical/radiologic features
Affects alveoli, interstitium, capillaries

Pathogenesis:

Initial inflammation (alveolitis) → neutrophil recruitment
Type I pneumocyte damage → Type II cell proliferation
Progressive fibrosis → honeycomb lung

Clinical Features:

Exertional dyspnoea, dry cough, tachypnoea, cyanosis
No wheezing

5. Pneumoconioses

Definition: Lung diseases due to inhalation of dust (mostly occupational)

Important Factors:

Particle size (<1 μm most harmful)
Solubility, amount, host clearance capacity
Associated smoking

Types of Responses:

Fibrous nodules (e.g., coal dust, silica)
Interstitial fibrosis (e.g., asbestosis)
Hypersensitivity reaction (e.g., beryllium)

Types of Pneumoconioses:

Agent	Diseases
Coal Dust	Simple CWP, Progressive Massive Fibrosis, Caplan’s syndrome
Silica	Silicosis, Caplan’s syndrome
Asbestos	Asbestosis, Mesothelioma
Organic Dusts	Farmer’s lung, Bagassosis, Bird-fancier’s lung

Coal Workers’ Pneumoconiosis (CWP)

Most common form
Seen in coal miners after prolonged exposure (20–30 years)
Anthracosis: Benign, asymptomatic carbon accumulation

Stages:

Simple CWP:
- <5 mm coal macules
- Mostly upper lobes
- No alveolar wall destruction
Progressive Massive Fibrosis (PMF):
- 2 cm fibrotic black masses
- Bilateral, upper zones
- May cavitate due to TB or necrosis
Caplan’s Syndrome:
- CWP + rheumatoid nodules in lungs

Pathogenesis:

Macrophage ingestion of dust → inflammation & fibrosis via:
- Free radicals
- Cytokines (IL-1, TNF, PDGF)
- Fibroblast proliferation

Microscopy:

Macrophages filled with carbon
Reticulin & collagen increase
Fibrotic nodules with dense collagen in PMF

Silicosis

Definition:

Silicosis is a chronic lung disease caused by long-term inhalation of crystalline silica dust.
Historically known as “knife grinders’ lung.”

Occupational Exposure:

High-risk jobs: Miners (granite, sandstone, coal, tin, copper), quarry workers, sandblasters, foundry workers, ceramic and slate/pencil/agate grinders.
In India: ~3 million workers are at risk, especially in construction and agate industries.

Forms:

Chronic Silicosis: Most common, associated with collagenous nodules.
Accelerated Silicosis: Acute form resembling alveolar proteinosis, showing irregular fibrosis and lipoproteinaceous exudate.

Pathogenesis:

Inhaled silica particles (0.5–5 μm) reach alveoli → phagocytosed by alveolar macrophages → macrophage necrosis.
Repetitive cycle of phagocytosis → necrosis.
Dust transported to lymphatics and lymph nodes → induces immune cell aggregation (T/B lymphocytes, fibroblasts).
Quartz (crystalline silica) is highly fibrogenic.
Macrophage death triggers release of IL-1 and growth factors → fibroblast proliferation → collagen deposition.

Morphologic Features:

Gross:

Hard, fibrotic nodules (1–5 mm) in upper lobes.
May co-contain coal dust.
Pleura thickened and adherent; egg-shell calcifications visible on X-ray.
Possible complications: TB, Caplan’s syndrome (rheumatoid pneumoconiosis), cavitation.

Microscopy:

Silicotic nodules near respiratory bronchioles, pleura, and lymph nodes.
Nodules show central hyalinization, concentric collagen lamellae, dust-laden macrophages.
Birefringent silica particles visible under polarizing microscope.
Coalescence of nodules → progressive massive fibrosis.
Intervening lung shows emphysema.
Cavities: due to ischemic necrosis or TB/RA involvement.

Clinical Features:

Slow onset with dyspnoea and cough.
May show obstructive or restrictive lung disease pattern.
Common complications: TB, Caplan’s syndrome, cor pulmonale.
Radiology: Fine to coarse nodularity, egg-shell calcification.
No increased risk of bronchogenic carcinoma.

Asbestosis

Forms of Disease:

Asbestosis (lung fibrosis)
Pleural lesions (effusion, plaques, fibrosis)
Tumors (bronchogenic carcinoma, mesothelioma)

Important Forms of Asbestos:

Chrysotile (serpentine) – flexible, common
Crocidolite, Amosite (amphibole) – rigid, more carcinogenic

Microscopy:

Interstitial fibrosis, asbestos bodies (beaded/dumbbell-shaped).
Pleural plaques: hyalinized, may calcify.
Tumors: ↑ risk of bronchogenic carcinoma, mesothelioma.

Berylliosis

Types:

Acute – Exudative pneumonitis, resolves with removal of exposure.
Chronic – Non-caseating granulomas (like sarcoidosis), often 20+ years after exposure.

Histology:

Granulomas with birefringent crystals, Schaumann bodies, and asteroid bodies.

Hypersensitivity Pneumonitis (Allergic Alveolitis)

Etiology:

Inhalation of organic antigens: thermophilic actinomycetes (hay, sugarcane), bird proteins, barley, moldy wood, etc.

Examples:

Farmer’s lung, Bird-fancier’s lung, Bagassosis, Mushroom worker’s lung, Silo-filler’s disease.

Pathology:

Type III (immune complex) or Type IV (delayed hypersensitivity).
Alveolar wall inflammation, granulomas in early stage; fibrosis and honeycombing in chronic cases.

Pulmonary Infiltrates with Eosinophilia (PIE Syndrome)

Causes:

Löffler’s syndrome – transient shadows, mild symptoms.
Tropical eosinophilia – due to helminths (filaria, ascaris).
Chronic eosinophilia – drugs, fungi, asthma.
Idiopathic eosinophilic pneumonia
Hypereosinophilic syndrome

Microscopy:

Alveolar walls and lumina filled with eosinophils, lymphocytes, granulomas possible.

Goodpasture’s Syndrome

Definition:

Autoimmune condition with pulmonary haemorrhage + rapidly progressive glomerulonephritis.

Pathogenesis:

Anti-GBM antibodies targeting shared antigen in lung and kidney basement membrane.

Microscopy:

Haemorrhage, necrosis, later fibrosis and haemosiderin-laden macrophages.

Clinical:

Young males, haemoptysis, anaemia, respiratory failure → later renal failure.

Pulmonary Alveolar Proteinosis

Definition:

PAS-positive, lipid-rich material fills alveoli.

Etiology:

May relate to silica, hematologic malignancies, macrophage dysfunction.

Histology:

Homogenous granular eosinophilic material, cholesterol clefts, minimal inflammation.

Tumours of the Lungs

I. Overview

Lungs can be affected by both benign and malignant tumours.
Bronchogenic carcinoma accounts for 95% of all primary lung tumours.
The lungs are also the most common site for metastases from other cancers.

II. WHO Classification of Lung Tumours

A. Epithelial Tumours

Benign: Papilloma, Adenoma
Dysplasia & Carcinoma in Situ
Malignant (Bronchogenic carcinoma):
1. Squamous cell carcinoma
2. Small cell carcinoma (oat cell, intermediate, combined)
3. Adenocarcinoma (acinar, papillary, bronchioloalveolar, solid with mucus)
4. Large cell carcinoma
5. Adenosquamous carcinoma
Other Carcinomas:
- Pulmonary neuroendocrine tumour (carcinoid)
- Bronchial gland carcinomas (adenoid cystic, mucoepidermoid)

B. Soft Tissue Tumours

Fibroma, leiomyoma, lipoma, haemangioma, etc.

C. Pleural Tumours

Benign & malignant mesothelioma

D. Miscellaneous

Carcinosarcoma, pulmonary blastoma, melanoma, lymphoma

E. Secondary Tumours

Metastatic cancers from other sites

III. Bronchogenic Carcinoma

A. Incidence & Classification

Most common cancer in men and leading cause of cancer deaths.
Peak incidence: 55–65 years.
5 Main Histologic Types:
1. Squamous cell carcinoma
2. Small cell carcinoma
3. Adenocarcinoma (now most common subtype)
4. Large cell carcinoma
5. Adenosquamous carcinoma
Therapeutic Classification:
- Small Cell Carcinoma (SCC): 20–25%
- Non-Small Cell Carcinoma (NSCC): 70–75%
  - Includes squamous, adeno-, large cell
- Combined Patterns: 5–10%

IV. Etiology

1. Smoking (Most important factor)

80% of lung cancers occur in smokers.
Dose-dependent risk: 60–70x risk in heavy smokers
Cessation reduces but never eliminates risk.
Strongest link: Squamous & Small Cell types
Carcinogens in smoke: Polycyclic hydrocarbons, nitrosamines

2. Other Risk Factors

Air pollution
Occupational exposure (asbestos, uranium, nickel, beryllium, arsenic)
Vitamin A deficiency
Chronic scarring (TB, fibrosis, infarcts)

V. Molecular Pathogenesis

Oncogene Activation:
- K-RAS, EGFR, BRAF, MYC, PIK3CA
Tumour Suppressor Gene Inactivation:
- p53, Rb, p16, RASSF1A (on chromosome 3p)
Autocrine Factors & Nicotine:
- Nicotine promotes tumour growth via acetylcholine receptors.
Inherited Risk:
- Li-Fraumeni syndrome (p53), Retinoblastoma (Rb), family history
Molecular Therapy Targets:
- EGFR mutations → EGFR-TKI
- VEGF overexpression → Anti-VEGF therapy
- Proteomic signatures for future personalized diagnosis

VI. Morphologic Types

A. Gross Types

Hilar Tumours (Central):
- Arise in main/segmental bronchi
- Grey-white friable mass
- Commonly causes obstruction, cavitation
Peripheral Tumours:
- Commonly adenocarcinomas
- Often located near lung periphery, appear mucoid

B. Histologic Types

Squamous Cell Carcinoma:
- Arises in large bronchi
- Strong link with smoking
- Shows keratinization or intercellular bridges
- May show spindle cell variant
Small Cell Carcinoma:
- Central location, highly malignant
- Shows neuroendocrine markers (Chromogranin, NSE)
- 3 Subtypes:
  - Oat cell
  - Intermediate cell
  - Combined
Adenocarcinoma:
- Most common in women and non-smokers
- Types:
  - Acinar
  - Papillary
  - Bronchioloalveolar (grows along alveoli)
  - Solid (with mucin vacuoles)
Large Cell Carcinoma:
- Undifferentiated, aggressive
- Large nuclei, abundant cytoplasm
Adenosquamous Carcinoma:
- Features of both squamous & adenocarcinoma
- Often peripheral, scar-related

VII. Spread

Direct Invasion:
- Bronchus → Pleura → Pericardium → Great vessels
- Pancoast tumour: Apical lung cancer → brachial plexus, sympathetic chain
Lymphatic Spread:
- Hilar → Mediastinal → Supraclavicular nodes
Haematogenous Spread:
- Liver > Adrenals > Bones > Brain > Other organs

VIII. Clinical Features

Local Symptoms:
- Cough, chest pain, haemoptysis, dyspnoea
Bronchial Obstruction:
- Leads to pneumonia, abscess, bronchiectasis
Metastatic Symptoms:
- Bone pain, SVC syndrome, neurologic signs
Paraneoplastic Syndromes:
- Ectopic hormone production:
  - ACTH → Cushing’s
  - ADH → Hyponatraemia
  - PTH → Hypercalcaemia
  - Calcitonin → Hypocalcaemia
  - Gonadotropins → Gynaecomastia
- Others:
  - Clubbing, osteoarthropathy
  - Polymyositis, neuropathies
  - Thrombophlebitis, coagulopathies

IX. Differential Diagnosis of Haemoptysis

Infectious: TB, abscess, pneumonia, bronchiectasis
Neoplastic: Lung cancer, bronchial adenoma
Others: PE, LV failure, mitral stenosis, trauma, PPH

X. TNM Staging & Prognosis

Occult: Malignant cells only
Stage I: Tumour < 3 cm, no distant spread
Stage II: Tumour > 3 cm, ipsilateral node involvement
Stage III: Invasion of structures or distant spread

Prognosis

5-year survival: ~15%
Best prognosis: Adenocarcinoma & Squamous Cell (if localized)
Worst prognosis: Small Cell (highly aggressive, metastatic early)

HAMARTOMA

Definition: A benign, tumor-like lesion made of disorganized but mature lung tissue elements.
Incidental Finding: Often found incidentally on chest X-ray as a coin lesion.
Types:
1. Chondromatous Hamartoma (more common)
  - Solitary, peripheral, spherical mass (2–5 cm)
  - Contains cartilage, fibrous and fat tissue, and bronchial epithelium
  - Usually asymptomatic
2. Leiomyomatous Hamartoma
  - Multiple small nodules (1–2 mm), near pleura
  - Made of smooth muscle and bronchiolar structures

METASTATIC LUNG TUMOURS

More common than primary lung cancers
Spread by:
- Blood (hematogenous) → most common
- Lymphatics
- Direct extension
Common appearance: Peripheral, multiple/single nodular masses (“cannon-ball secondaries”).
Primary sites:
- Carcinomas: bowel, breast, thyroid, kidney, pancreas, liver, lung
- Others: osteogenic sarcoma, neuroblastoma, Wilms' tumour, melanoma, lymphomas, leukaemias

PLEURA

NORMAL STRUCTURE

Visceral pleura: Covers lungs and fissures
Parietal pleura: Lines chest wall, mediastinum, diaphragm
Pleural cavity: Thin space with <15 mL of clear fluid
Lining: Single layer of mesothelial cells with connective tissue beneath

PLEURAL INFLAMMATIONS (PLEURITIS / PLEURISY)

1. Serous, Fibrinous & Serofibrinous Pleuritis

Causes: TB, pneumonia, lung abscess, infarcts, autoimmune diseases (RA, SLE), uraemia, radiation
Symptoms: Chest pain, pleural friction rub
Course: Usually resolves; repeated attacks → fibrosis and adhesions

2. Suppurative Pleuritis (Empyema Thoracis)

Purulent infection of pleural cavity (pus)
Causes: Spread from lung infections, abscesses, trauma
Complications: Fibrosis, adhesion, respiratory difficulty, calcification

3. Haemorrhagic Pleuritis

Inflammatory bloody effusion, different from haemothorax
Causes: Metastases to pleura, bleeding disorders, rickettsial diseases

NON-INFLAMMATORY PLEURAL EFFUSIONS

1. Hydrothorax

Clear, serous fluid (transudate) in pleural cavity
Causes: CHF (most common), renal/liver failure, Meig’s syndrome, tumors
Findings: Often bilateral; large effusion may shift trachea, cause dyspnoea

2. Haemothorax

Pure blood in pleural cavity
Causes: Trauma, ruptured aortic aneurysm
Complication: Clotting → fibrosis if not drained promptly

3. Chylothorax

Milky lymphatic fluid accumulation
Causes: Thoracic duct rupture or obstruction (e.g. lymphomas)
Usually on left side

PNEUMOTHORAX

Air in pleural cavity → lung collapse

Types:

Spontaneous
- Common with emphysema, asthma, TB, bronchiectasis
- In young: idiopathic rupture of subpleural blebs
Traumatic
- Due to chest injury, surgery, ruptured esophagus/stomach
Therapeutic
- Previously used for TB treatment by inducing lung collapse

Complication:

Tension Pneumothorax: One-way air entry, no exit
→ Mediastinal shift, respiratory distress
→ Needs emergency decompression

TUMOURS OF PLEURA

1. Primary Pleural Tumour: Mesothelioma

A. Benign (Solitary) Mesothelioma

Also called pleural fibroma
No asbestos link
Small (<3 cm), firm, whorled fibrous mass
Microscopy: Dense collagen with fibroblasts; rarely lined by mesothelium
Asymptomatic, sometimes causes hypoglycemia or osteoarthropathy
Prognosis: Curable with removal

B. Malignant (Diffuse) Mesothelioma

Highly aggressive, poor prognosis
Strongly associated with asbestos exposure (esp. crocidolite)
Latency: Appears 20–40 years after exposure
No synergistic effect with smoking (unlike bronchogenic carcinoma)
Other cause: SV40 virus (implicated)
Gross: Thick, white, fleshy coat over pleural surfaces
Histologic Types:
- Epithelial: Adenocarcinoma-like tubular/papillary pattern
- Sarcomatoid: Spindle-shaped cells, fibrosarcoma-like
- Biphasic: Mixture of both
Clinical features: Chest pain, dyspnoea, pleural effusion
Spread: Lung invasion, lymphatics, liver metastasis
Prognosis: 50% die within 1 year

2. Secondary Pleural Tumours

More common than primary
Causes: Lung, breast (via lymphatics), ovary (haematogenous)
Appearance: Multiple nodules over pleura