week 8 Flashcards
(62 cards)
1
Q
Asthma definition
A
Increased responsiveness of airways to various stimuli and is manifested by inflammation and widespread narrowing of the airways that changes in severity, either spontaneously or as a result of treatment
2
Q
Asthma aetiology and risk factors
A
- Genetic predisposition (e.g., family history of atopy, asthma) (heredity)
- Environmental exposures (e.g., allergens, pollutants, viral infections)
- Occupational sensitisers (e.g., chemicals, dust)
- Associated comorbidities (e.g., allergic rhinitis, atopic dermatitis)
- Social determinants (e.g., poor housing, pollution, systemic racism)
- Smoking tobacco
- Temp changes
- Stress
- Urbanisation
3
Q
Asthma Epidemiology
A
- Around 2.8 million people in AUS (11%)
- 300 million globally
- 10% in children and adolescents, 6-7% in adults
4
Q
asthma clinical manifestation
A
- Classic symptoms: wheezing, dyspnoea, cough (often nocturnal), chest tightness
- Symptoms are episodic, often triggered by exercise, allergens, cold air, viral infections
- Exacerbations may be life-threatening in severe cases
- Physical signs: polyphonic expiratory wheezing, prolonged expiration, accessory muscle use in severe attacks
5
Q
Asthma Pathogenesis
A
- Defined by intermittent bronchospasm causing symptoms such as wheezing and dyspnoea, and characterised by airway inflammation, airway hyper-responsiveness, and mucus hypersecretion
- Contribute to variable airflow obstruction, but with heterogeneous underlying inflammatory mechanisms
6
Q
Asthma Pathophysiology
A
- Airway inflammation
- Inflammatory cells involved: Mast cells, Eosinophils, T lymphocytes
- These cells infiltrate the bronchial mucosa and contribute to inflammation and tissue injuries
This inflammation leads to:
- Oedema
- Increased mucus production
- Desquamation of epithelial cells
- Increased vascular permeability
π Clinical relevance: This inflammatory process underlies the reversible airway obstruction seen in asthma - Bronchial Hyperresponsiveness (BHR)
- Defined as an exaggerated bronchoconstrictor response to various stimuli (e.g., allergens, exercise, cold air, irritants, thunderstorms).
- This is a hallmark of asthma and contributes to episodic symptoms - Bronchoconstriction
Triggered by:
- Direct exposure to allergens
- Non-specific irritants
- Exercise
- Leads to narrowing of the airways, causing wheezing, dyspnoea, chest tightness, cough
π‘ Mechanism: Inflammatory mediators (e.g., histamine, leukotrienes) released by mast cells cause smooth muscle contraction - Mucus Hypersecretion
- Goblet cell hyperplasia leads to excess mucus production
- Mucus plugs may form and obstruct bronchioles, worsening airflow limitation - Airflow obstruction
Airflow limitation results from:
- Bronchospasm
- Mucosal oedema
- Mucus plugging
This obstruction is typically reversible, either spontaneously or with treatment. Detected by spirometry as a reduced FEV1 and reduced FEV1/FVC ratio, with improvement after bronchodilator use - Reversibility and Variability
Asthma is characterised by:
- Reversible airflow limitation
- Day-to-day and diurnal variability in symptoms
- Symptoms often worse at night or early morning - Contributing Systemic Factors
- Atopy: Strongly associated with asthma, especially early-onset forms. Involves a heightened IgE response to environmental allergens.
- Obesity: Independently associated with increased asthma risk and severity, possibly through systemic inflammation and mechanical effects.
- Environmental pollutants: May exacerbate inflammation, especially in genetically susceptible individuals.
- Smoking and infections: Worsen inflammation and contribute to airway remodelling
7
Q
COPD defintion
A
heterogenous lung condition characterised by chronic respiratory symptoms due to abnormalities of the airway and/or alveoli that causes persistent, often progressive airflow obstruction
8
Q
COPD aetiology
A
- Cigarette smoking (90% of cases in Australia)
- Air pollution (including biomass smoke and bushfire smoke)
- Occupational exposure to dusts and fumes
- Recurrent childhood respiratory infections
- Genetic factors: Ξ±β-antitrypsin deficiency
- Low socioeconomic status
9
Q
COPD Epidemiology
A
- COPD is the foremost cause of preventable hospitalisations amongst chronic health conditions.
- It is the 5th leading cause of death in Australia and the 3rd leading specific cause of total disease burden.
- Of the 8.5 million (34%) people in Australia estimated to have chronic respiratory conditions, 2.5% people had COPD (ABS 2023)
10
Q
Prevalence of COPD
A
- Similar for men and women overall; increases gradually with age until 45β54 years, after which prevalence increases more sharply.
- The prevalence of COPD among First Nations people is estimated to be 2.3 times as high as in the non-First Nations population, and the mortality rate of COPD among First Nations Australians was 2.7 times as high as the non-First Nations rate.
- COPD prevalence is higher for people living in Outer regional and remote areas than people living in major cities in Australia,
- COPD prevalence is higher for people living in areas of most disadvantage (lowest socioeconomic areas).
- People living with chronic respiratory conditions often have other chronic, long-term conditions, known as βcomorbidityβ. Chronic conditions associated with COPD include mental and behavioural conditions and arthritis
11
Q
pathogeneis of COPD
A
- The predominant pathologic changes of COPD are found in the airways, with changes in the lung parenchyma and pulmonary vasculature
12
Q
subtypes of COPD
A
- Chronic Bronchitis
- Clinical diagnosis: productive cough for β₯3 months/year for β₯2 consecutive years
- Prominent mucus production, airway narrowing
- ABGs: chronic compensated respiratory acidosis in later stages - Emphysema
- Destruction of alveolar walls β decreased surface area for gas exchange
- Hyperinflation and air trapping β barrel chest, dyspnoea
- ABGs: hypoxaemia, later hypercapnia with acidosis
13
Q
COPD pathologic features
A
Airways
- Chronic inflammation leads to increased numbers of goblet cells, mucus gland hyperplasia, fibrosis, and narrowing in and loss of small airways
ο§ Specifically, emphysema: airway collapse frequently occurs due to the loss of tethering caused by emphysematous destruction of alveolar walls
ο§ Specifically chronic bronchitis: mucus hypersecretion, an increased number of goblet cells and enlarged submucosal glands
Chronic airway inflammation in chronic bronchitis and emphysema is characterised by the presence of:
- CD8+ T-lymphocytes, neutrophils, and CD68+ monocytes/macrophages
Lung parenchyma
- Respiratory bronchiole, alveolar ducts, alveolar sacs, and alveoli and associated capillaries and interstitium
- Emphysema affects the structures distal to the terminal bronchiole - respiratory bronchiole, alveolar ducts, alveolar sacs, and alveoli - collectively as the acinus
- The part of the acinus that is affected by permanent dilation or destruction determines the subtype of emphysema.
Proximal acinar emphysema
= Abnormal dilation or destruction of respiratory bronchiole, the central portion of the acinus
- Commonly associated with cigarette smoking and coal workersβ pneumoconiosis.
- Most common emphysema subtype seen in patients with COPD
Panacinar emphysema:
= Enlargement or destruction of all parts of the acinus.
- Characteristic of alpha-1 antitrypsin deficiency
Distal acinar emphysema:
= Alveolar ducts predominantly affected
- May occur alone or in combination with proximal acinar and panacinar emphysema
Pulmonary vasculature
- Changes in the pulmonary vasculature in COPD include intimal hyperplasia and smooth muscle hypertrophy/hyperplasia, which are thought to be due to chronic hypoxic vasoconstriction of the small pulmonary arteries
14
Q
clinical man of COPD
A
- Dyspnoea (especially on exertion)
- Chronic cough
- Sputum production
- Early symptoms: exertional dyspnoea
- Less common: Wheezing and chest tightness
15
Q
what is chronic bronchitis
A
Chronic cough and sputum production for at least three months in each of two consecutive years in the absence of other conditions that can explain the symptoms
16
Q
Aetiology of CB
A
same as COPD
17
Q
Epidemiology of CB
A
- 3% to 7% of healthy adults
- Increasing prevalence - increasing age, smoking, occupational exposure, and socioeconomic status
18
Q
clinical man of CB
A
- Dyspnoea, productive cough, cyanosis
19
Q
CB pathophysiology
A
narrowing of airway, enlargement of submucosal gland, mucus plug, inflam of epithelium, hyperinflation of alveoli, infiltration of inflam cells and release of cytokines leading to continuous bronchial irritation and inflam as well as breakdown in lung elastic tissue
20
Q
Emphysema defintion
A
= Enlargement of air spaces distal to terminal bronchioles with destruction of their walls
- Abnormal, permanent enlargement of gas-exchange airways
- Accompanied by destruction of alveolar walls
- Airflow limitation is loss of elastic recoil
21
Q
aetiology of emphysema
A
- Same as COPD (cigarette, smoking, air pollution, childhood respiratory infections)
22
Q
epidemiology of emphysema
A
unclear
23
Q
clinical man of emphysema
A
dyspnoea early in disease wheeze common and barrel chest
24
Q
pathophysiology of emphysema
A
inflam of airway epithelium due to irritants, infiltration of inflam cells and release of cytokines which causes systemic effects (muscle weakness) as well as breakdown of lung elastic tissue
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chronic suppurative lung disease what is it
= Chronic suppurative lung disease (CSLD) and bronchiectasis are clinical syndromes, with respiratory signs or symptoms of a persistent productive cough, dyspnoea, airway reactivity and recurrent chest infections
- Chronic Suppurative Lung Disease (CSLD) refers to a clinical syndrome, primarily in children, characterised by chronic or recurrent wet/productive cough and lower respiratory infections in the absence of radiological evidence of bronchiectasis
- It reflects early airway inflammation and infection that may precede permanent structural damage
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Bronchiectasis what is it
= Chronic suppurative lung disease (CSLD) and bronchiectasis are clinical syndromes, with respiratory signs or symptoms of a persistent productive cough, dyspnoea, airway reactivity and recurrent chest infections
- Bronchiectasis refers to a clinical syndrome in children/adolescents or adults that involves irreversible dilatation of the bronchi due to structural airway injury
- It is diagnosed based on clinical symptoms (chronic productive cough, recurrent infections) and confirmed by high-resolution chest CT revealing bronchial dilatation
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aetiology of CSLD and Bronchiectasis
The Bronchiectasis and CSLD are the result of various insults that damage the bronchial wall, impair mucociliary clearance, and promote recurrent infections. Key causes include:
- Post-infectious (e.g., pneumonia, tuberculosis, pertussis)
- Cystic fibrosis (CF) or CFTR-related disorders
- Primary ciliary dyskinesia (PCD)
- Allergic bronchopulmonary aspergillosis (ABPA)
- Autoimmune and systemic diseases (e.g., rheumatoid arthritis, SjΓΆgrenβs syndrome)
- Immunodeficiencies (e.g., CVID, IgG subclass deficiencies)
- Foreign body aspiration or airway obstruction (e.g., tumors, broncholiths)
- Alpha-1 antitrypsin deficiency
- Nontuberculous mycobacterial (NTM) infections
- Recurrent aspiration or reflux
- Tracheobronchomalacia and congenital syndromes (e.g., Mounier-Kuhn, Young syndrome)
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Epidemiology of CSLD and bronchiectasis
- The prevalence of CSLD and bronchiectasis is not accurately known and data varies considerably throughout the world with a very high incidence in the Indigenous populations of New Zealand and Australia
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Pathogenesis of CSLD and bronchiectasis
- CSLD and bronchiectasis are characterised by a self-perpetuating cycle of airway damage involving infection, inflammation, impaired mucociliary clearance and with bronchiectasis, notable structural lung changes. This cycle is often referred to as the "vicious vortex"
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clinical man of CSLD and bronchiectasis
wet cough, recurrent lower tract infection, dyspnoea, crackles, wheeze, fatigue, obstructive, Reversible for CSLD and irreversible for bronchiectasis
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steps in CSLD and bronchiectasis
1. Initial airway insult
The pathogenic cascade often begins with injury to the airway epithelium, caused by:
- Severe lower respiratory infections (e.g., pneumonia, pertussis, tuberculosis)
- Airway obstruction (tumours, mucus plugs, aspirated foreign bodies)
- Congenital or acquired immune defects (e.g., CVID, IgG subclass deficiencies)
- Impaired host defence mechanisms (e.g., CFTR mutations, ciliary dyskinesia)
This initial injury:
- Compromises epithelial integrity
- Triggers an aberrant immune response
- Disrupts mucociliary clearance
2. Impaired mucociliary clearance
Damage to the ciliated epithelium impairs the mucociliary escalator, leading to mucus stasis. Factors contributing to this impairment include:
- Ciliary damage or dysfunction impairs mucus transport (as in primary ciliary dyskinesia)
- Goblet Cell Hyperplasia: resulting in excessive mucus production
- CFTR dysfunction (seen in cystic fibrosis and CFTR-related disorders) dehydrates the airway surface liquid, increasing mucus viscosity
Stagnant mucus becomes a breeding ground for pathogens, facilitating chronic infections
3. Chronic Infection
Persisting mucus fosters chronic colonisation by pathogens such as:
- Pseudomonas aeruginosa (notorious for biofilm formation, virulence factors like pyocyanin) the
- Haemophilus influenzae
- Staphylococcus aureus
- NTM (e.g., Mycobacterium avium complex)
- Fungal elements (e.g., Aspergillus in ABPA)
Key features of chronic infection:
- Biofilms β resist immune clearance and antibiotics
- Disruption of epithelial repair
- Promotion of chronic neutrophilic inflammation
4. Neutrophilic Inflammation
Persistent infection activates innate immune cells, especially neutrophils, which release:
These responses:
- Promote mucosal ulceration, oedema and angiogenesis
- Correlate with disease severity, sputum purulence and exacerbation risk
5. Structural lung damage
Chronic inflammation and proteolysis drive airway remodelling:
NOTE: CSLD may show similar inflammation and mucus dysfunction without radiological evidence of dilation, suggesting earlier or milder disease
6. Contributing factors and amplifiers
Several factors exacerbate disease progression:
The pathogenesis can be visualised as a vicious vortex
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Cystic Fibrosis definition
Cystic fibrosis (CF) is an autosomal recessive multisystem disorder caused by mutations in the CFTR gene. It is characterised by defective chloride and bicarbonate transport across epithelial surfaces, resulting in dehydrated, thick secretions in the lungs, gastrointestinal tract, pancreas, biliary system, reproductive organs, and sweat glands. CF predominantly leads to progressive lung disease, pancreatic insufficiency, malnutrition, and premature mortality.
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CF aetiology
- Genetic Basis: Caused by biallelic pathogenic mutations in the CFTR gene (located on chromosome 7q31.2).
- Most Common Mutation: F508del accounts for ~70% of mutations in Caucasians.
- Inheritance Pattern: Autosomal recessive
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CF Epidemiology
- Prevalence: Most common life-limiting autosomal recessive disease in Caucasians (~1 in 2500β3500- live births).
- Carrier Frequency: 1 in 25 among individuals of European descent.
- Life Expectancy: Median predicted survival exceeds 50 years with current CFTR modulator therapy.
- Ethnic Variation: Rare in non-European populations but increasingly recognised due to global migration and newborn screening
- In Australia, CF is the most common, life-limiting genetic condition. Over 3,730 people are living with CF in Australia and 1 in 25 people carry the recessive CF gene change
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CF Pathogenesis
- CF pathogenesis involves abnormal epithelial ion transport and a "vicious cycle" of infection, inflammation, and tissue destruction, especially in the lungs.
1. CFTR Dysfunction
CFTR protein is a chloride/bicarbonate channel regulated by cAMP/PKA.
Loss of CFTR function β β chloride and bicarbonate secretion, β ENaC sodium absorption β dehydrated airway surface liquid.
Consequences:
* Mucus stasis
* Ciliary dysfunction
* Airway obstruction
2. Airway Inflammation and Infection
* Early neutrophilic inflammation occurs even before infection in infants.
* Persistent colonization with pathogens (e.g., Pseudomonas aeruginosa, Staph. aureus):
* Forms biofilms
* Increases oxidative stress
* Releases proteases (e.g., elastase)
* NETs, myeloperoxidase (MPO), and reactive oxygen species (ROS) exacerbate damage.
3. Tissue Destruction and Bronchiectasis
Neutrophilic inflammation causes:
* Bronchial wall thickening
* Irreversible airway dilation (bronchiectasis)
* Loss of elastin and airway remodelling
4. Extrapulmonary Effects
* Pancreatic insufficiency: Thick secretions block pancreatic ducts β enzyme loss β fat malabsorption, malnutrition.
* CF-related diabetes (CFRD): Progressive Ξ²-cell loss and insulin deficiency.
* Biliary cirrhosis: Obstruction of intrahepatic bile ducts.
* Male infertility: Congenital absence of vas deferens (CBAVD).
* Intestinal obstruction: Meconium ileus, distal intestinal obstruction syndrome (DIOS).
5. Genetic Modifiers
* Influence phenotype and severity:
* TGFB1: β inflammation and lung damage
* MBL2: β risk of infection
* SLC26A9, TNF, TCF7L2: Affect risk of CFRD and pulmonary progression
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clinical man of CF
1. Respiratory System
* Chronic productive cough
* Wheezing
* Recurrent bronchitis or pneumonia
* Hemoptysis (in advanced disease)
* Dyspnea and hypoxia
* Digital clubbing
* Progressive bronchiectasis
* Colonisation with P. aeruginosa or B. cepacia complex
* Nasal polyps and chronic sinusitis
2. Gastrointestinal and Nutritional
* Meconium ileus (neonates)
* Failure to thrive
* Fatty stools (steatorrhea)
* Malnutrition and vitamin deficiencies (A, D, E, K)
* Distal intestinal obstruction syndrome (DIOS)
* Hepatobiliary disease (e.g., cirrhosis, gallstones)
* CF-related diabetes mellitus
3. Reproductive
* Male infertility (CBAVD)
* Reduced female fertility due to cervical mucus abnormalities
4. Other
* Salt loss syndromes (hyponatremic dehydration)
* Osteopenia/osteoporosis
* Chronic sinus disease
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Bronchiectasis what is it
- Result of infectious insult or impaired host defence
Definition: Bronchiectasis is an abnormal permanent dilation and distortion of bronchi and bronchioles result of chronic inflammation of airways
Leads to:
- Progressive destruction of bronchial walls and lung tissue
- Increased sputum production, recurrent exacerbations and impaired quality of life Anatomic abnormality rather than a single disease
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Epidemiology of Bronchiectasis
- Limited data on incidence, diagnosis and mortality rates of bronchiectasis in Australia
- Frequently in less affluent communities and in Indigenous communities
- 1470/100,000 in central Australian Aboriginal children
- Prevalence increases with age (> 60 years) in US and Europe
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Aetiology of Bronchiectasis
infections, bronchial obstruction, acquired bronchial obstruction such as tumours, foregin bodies, COPD, Mucoid impaction
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Pathophysiology of Bronchiectasis
1. Infectious insult and impaired mechanisms
2. Inflammatory Response: immune response involving neutrophils, lymphocytes and macrophages
3. Neutrophils and Elastase: progress airway destruction (microbial colonisation, affect cilia and mucus secretion)
4. Sputum/Mucus: physical properties β tenacious due to higher concentrations of DNA and mucin
5. Can occur in parallel with COPD and asthma β worse prognosis
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Pathogenesis of Bronchiectasis
- Inflammatory processes damage cilia impairing mucociliary clearance
- Remaining bacteria remain in airways and colonise mucus
- Further inflammatory response to bacteria further inhibits ciliary function
- Damage occurs to elastic and muscular tissue of the bronchial walls stimulating further mucous production
- Loss of elastic and muscular tissue leads to dilation of the bronchi
- Dilated βfloppyβ airways reduce effectiveness of airway clearance causing this cycle to repeat causing disease progression
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clinical man of bronchiectasis
- Chronic cough
- Sputum
- Exacerbations
- Dyspnoea
- Rhinosinusitis
- Haemoptysis
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Pneumonia definition
inflammation of the lung parenchyma associated with alveolar filling by exudate
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aetiology of pneumonia
- Caused by inhalation of baxcertia, fungi, viruses or chemical agents
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epidemiology of pneumonia
- Age: 70+ years; infants aged 12 months and under 3 years
- Medical conditions e.g., diabetes, cancer or a chronic disease (lungs, heart, kidney or liver); Aboriginal and Torres Strait Islander people < 50 years, who have medical conditions that put them at higher risk, including people living with chronic lung disease
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Clinical Manifestations of Pneumonia
- Fever, chills, productive or dry cough, malaise, pleural pain and sometimes dyspnoea and haemoptysis; Auscultation: consolidation and inspiratory crackles
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Pathophysiology of Pneumonia
The Primary routes through which pathogens enter lower respiratory tract:
- Aspiration of oropharyngeal secretions
- Inhalation of airborne microorganisms
If pathogen moves past upper airway defence mechanisms
- Alveolar macrophage (phagocyte)
- If microorganism is virulent or in large enough numbers β overwhelmed
- Release of inflammatory mediators, cellular infiltration, and immune system activation
- Damages respiratory system's structural integrity
- Exudate accumulation in alveoli
- Impaired gas exchange, dyspnoea and hypoxaemia
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types of pneumonia
- Bronchopneumonia: bronchi and bronchioles to lower lobes
ο§ Patchy areas of consolidation - neutrophil collection in alveoli and bronchi.
- Lobar pneumonia: exudative inflammation of entire lobe
ο§ Uniform consolidation with a complete or near complete consolidation of a lobe of a lung
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Tuberculosis what is it
An infectious, inflammatory systemic disease affecting the lungs however may also disseminate to other organs
Infection is caused by bacterial pathogen Mycobacterium tuberculosis
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Tuberculosis Epidemiology
In Australia 5.8 cases per 100,000 population (2018). Northern Territory has the highest rate of TB in Australia
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risk factors of tuberculosis
Age, immunosuppression, alcohol and illicit drug use, smoking tobacco, malnutrition, diabetes mellitus, health-care work and incarceration; migration
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clinical man of tuberculosis
coughing, fever, weight loss and night sweats.
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Pathophysiology of Tuberculosis
- Colonisation of Mycobacterium tuberculosis.
- Infection transmitted through airborne droplets and lodge in lung periphery
ο§ Multiply and cause lung inflammation
ο§ Bacteria migrate through lymphatics and become lodged in lymph nodes
- Inflammation - activation of alveolar macrophages and neutrophils
ο§ Engulf bacteria and bodyβs defence mechanisms isolate and prevent their spread
ο§ Neutrophils and macrophages seal off colonies of bacteria, forming granulomatous lesions (tubercles)
ο§ Infected tissues within tubercles die, forming cheese-like material that is necrotic
ο§ Scar tissue grows around tubercles, completing isolation of bacteria
ο§ Immune response is complete after 10 days, preventing further spread
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SARS-CoV-2, 2019-nCoV what is it
- Coronavirus is a single-strand RNA virus - attaches to a receptor, penetrating cell membrane and undergoing replication of RNA, which are released from infected cell
- SARS-CoV-2 binds to angiotensin-converting enzyme (ACE2) receptor in epithelial cells in respiratory tract
spike-like protein also attaches to ACE2 in heart, blood vessels, kidney, liver and lining of gastrointestinal tract
- Angiotensin II increases inflammation, tissue damage and cell death in alveoli
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clinical man of SARS-CoV-2, 2019-nCoV
multitude of signs and symptom
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pathophysiology of SARS-CoV-2, 2019-nCoV
- COVID-19 virus infects the upper respiratory tract
virus migrates through respiratory conducting airways
S&S:
- Mild infection - fever, malaise and cough
- Severe infection - widespread system-level disease
ο§ Pulmonary infiltrates which causes changes to gas exchange
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infective lung disease aetiology
Pneumonia - infection of alveolar spaces (bacterial or viral or fungal)
tuberculosis - MTB complex (the bacteria)
SARS-CoV-2 - infection with novel coronavirus
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Infective lung disease pathogenesis
General Pathway:
1. Inhalation or aspiration of pathogens β colonisation of alveoli or bronchioles
2. Evasion of host defences β impaired mucociliary clearance, dysfunctional alveolar macrophages
3. Host immune response:
- Innate: neutrophils, macrophages, dendritic cells β cytokine release (e.g. IL-1, IL-6, TNF-Ξ±)
- Adaptive: T-cell activation, antibody production
4. Alveolar-capillary damage:
- β Vascular permeability β pulmonary oedema
- Inflammatory exudate β consolidation
5. Complications:
- Sepsis, ARDS, lung abscess, pleural effusion
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Pneumonia Pathogenesis
A. Pathogen Entry
* Inhalation of airborne droplets (e.g., Streptococcus pneumoniae, influenza)
* Aspiration of oropharyngeal flora or gastric contents
* Haematogenous spread from extrapulmonary infection sites (rare)
B. Host Defence Mechanisms
* Nasal hair, mucociliary clearance, cough reflex
* Alveolar macrophages & neutrophils
* Surfactant proteins, antimicrobial peptides
C. Failure of Host Defences
* Pathogens bypass barriers or overwhelm the immune system
* Risk factors: Smoking, viral infection, chronic illness, elderly age
D. Inflammatory Response
* Innate immune activation: Alveolar macrophages detect PAMPs (e.g., LPS, peptidoglycan).
* Release of proinflammatory cytokines: IL-1Ξ², TNF-Ξ±, IL-6.
* Recruitment of neutrophils β phagocytosis of pathogens.
* Neutrophil degranulation & ROS production β local tissue injury.
E. Alveolar Damage & Consolidation
* Accumulation of neutrophils, exudate, and fibrin in alveoli.
* Disrupted gas exchange β hypoxia.
* Typical pneumonia: Lobar consolidation (e.g., S. pneumoniae).
* Atypical pneumonia: Patchy interstitial infiltrates (e.g., Mycoplasma pneumoniae).
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Tuberculosis pathogenesis
Definition: A chronic granulomatous disease caused by Mycobacterium tuberculosis (MTB).
A. Transmission & Initial Infection
* Airborne droplet nuclei inhaled β reach alveoli.
* MTB phagocytosed by alveolar macrophages but resists intracellular killing.
B. Immune Evasion
* MTB inhibits phagosome-lysosome fusion and acidification.
* Survives within macrophages using complex lipids (cord factor, sulfolipids).
C. Adaptive Immunity Activation (Weeks Later)
* Antigen presentation triggers Th1 response.
* IFN-Ξ³ activates macrophages β improved killing.
* Formation of granulomas: central infected macrophages (some become multinucleated giant cells), surrounded by T-cells and fibroblasts.
D. Latent vs. Active TB
* Latent TB: Controlled infection; MTB dormant within granulomas.
* Reactivation: Granuloma breakdown β caseous necrosis β MTB spreads to lung/apex and systemically.
E. Pathological Hallmarks
* Caseating necrosis.
* Cavitation in advanced disease.
* Miliary TB: Hematogenous spread β tiny nodules in multiple organs.
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SARS-CoV-2 (COVID-19) pathogenesis
A. Viral Entry
* Spike (S) protein binds to ACE2 receptor on type II alveolar cells.
* Viral entry facilitated by TMPRSS2 protease.
B. Viral Replication & Evasion
* Replication within host cells β cell lysis.
* Evasion of innate immune detection via suppression of interferon (IFN) pathways.
C. Dysregulated Immune Response
* Release of proinflammatory cytokines (IL-6, TNF-Ξ±, IL-1Ξ²) β cytokine storm in severe cases.
* Massive monocyte and neutrophil infiltration.
* Endothelial activation β microvascular thrombosis and capillary leak.
D. Lung Injury
* Diffuse alveolar damage (DAD): characteristic of ARDS.
* Hyaline membrane formation, alveolar edema, pneumocyte desquamation.
* Thrombosis: Common in severe COVID-19, especially in small pulmonary vessels.
E. Long-term Sequelae
* Post-COVID fibrosis, persistent inflammation, long COVID symptoms
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