Respiratory Pathology

Lecture 17: Pneumonia

• Pneumonia: disease of the respiratory tract where alveoli becomes infected and filled with fluid as a result of bacteria invasion. The most common bacterium is the streptococcus pneumoniae and three criteria are required for infection.
- Organism must reach distal bronchial three
- Organism must survive and replicate
- Host response might exacerbate the situation
• Initial step: most bacteria usually first occupy the naopharynx and when the chance presents, migrate down to the lower air ways. However the lung defense is effective and is able to cure most infections.
• Mechanism to distal bronchi:
- Colonise and replicate at the oropharynx to be later aspirated down into the alveoli
- Inhalation directly in to alveoli
- Blood borne spread to alveoli (through circulation)
• Mechanism for survival and replication:
- Expulsion in mucus moved by cilia: inhibited by smoking, viral infections and bacterial toxins
- Phagocytosis: inhibited by capsule surrounding the bacteria
- Killing within phagocytic vacuole: inhibited by bacterial products, e.g. cell wall of mycobacterium tuberculosis
• Step one: bacteria colonize the oropharynx by sticking to the mucus at the back of the throat. It is possible for germs to penetrate through the mucus and settle at the apical surface of the epithelium.
• Step two: Micro-aspiration of the bacteria passes into the alveoli (bypasses the mucocillary apparatus). Replication of the bacteria initiates and release of the toxin pneumolysin kills surrounding alveolar cells and release their cytoplasmic content
• Step three: cellular content signals local macrophages to migrate to area of cell damage. The bacteria continues to replicate.
• Step four: upon reaching the alveoli, the macrophages passes between two epithelial cells to site of bacterial infection. Pneumolysin kills the macropahges, releasing the cells digestive contents and cytokines signals
• Step five: circulating neutrophils become attracted to the cytokine released by the macrophages (chemotaxis) and the capillaries become increasingly leaky due to the effect of the cytokines released by neutrophils and dead cell debris.
• Step six: alveoli becomes saturated with exudates and RBC. The term “red hepatization” is used to illustrate the red edema appearance of the liver.
• Step seven: neutrophils ingest and digest bacteria without capsules while leaving those with unattended.
• Step eight: B-lymphocyte on the other hand is capable of producing antigen-specific antibodies that bind to the capsule coat of the bacteria. Following this, neutrophils is then able to engulf bacteria with antibodies coated.
• Step nine: IgG is in the blood while IgA is secreted in saliva. Both these immunological factors aid the destruction of the pneumonia pathogen and allow neutrophils to finally bind and kill the bacteria
• Note:
- Pneumolysin is constantly made to kill the neutrophils. However when stimulated, the number of neutrophils increases dramatically and this is capable to out-compete and kill all the bacteria.
• Susceptible group: from 6 months to around 5 years of age, the risk of pneumonia is the greatest. This is because the non-self made B antibodies obtained from the mother will slowly be degraded and replaced with the baby’s own antibodies.
• Preventative measures:
- Inject bacterial antigen into body to stimulate immune response (the sugar cell wall of the top 8 bacterial strain that causes pneumonia is defended against)

Lecture 25: Asthma

• Asthma: narrowing of airway due to inflammation at any level
- Symptoms: shortness of breath, wheezing, cough
- Hyperventilation occurs as an response
- Varies with severity and time (day to day)
- Asthma is common but asthma death are very low
• Measuring asthma: spirometry used to measure changes in lung volume over time.
- With asthma, the FEV1 and FVC is both greatly reduced
- However FEV will decrease more proportionally (i.e. FEV1/FVC ratio decreases)
• Mechanism of asthma: air way narrowing in expiration leads to gas trapping and hyperinflation. Respiration now occurs at higher lung volume and work of breath increases. This produces the signs of breathlessness in both inspiration and expiration.
• Inflammation: asthma is an inflammatory disease with accumulation of a wide variety of cells in the airway wall, e.g. eosinophils, lymphocytes, mast cells (mains ones) and neutrophil, monocyte and basophils.
- Eosinophils is the most characteristic cell hence asthma can be called chronic eosinophilic bronchitis. Rare exceptions can occur
• Aetiology: inflammation can occur in all three situations, extending all the way through the wall to adventitia
- Bronchospasm: smooth muscle contraction
- Mucous plugging
- Airway wall edema or swelling: plasma leaks out of blood vessels and enter the lumen
• Pathology:
- Allergy (more common) and non-allergy pathways but both have same consequences and morphology. 90% of children have allergic asthma
- Allergic conditions: eczema (atopic dermatitis), hayfever (allergic rhinitis) and asthma. All conditions can be present with asthma but during early ages usually its eczema and hayfever.
- Asthma develop due to increase in immunoglobin E and increase in eosinophils
- Eosinophil role: produce de novo mediators (leukotrienes) and secrete granule mediators which are major basic protein that is toxic to epithelium (epithelial damage). Migration of eosinophil due to chemokines (most important is eotaxin) which is released by the airway in response to allergens
• Importance of IgE and eosinophil: these are essential in fighting parasite infections. IgE is used to target antigens such as locus dust mite, grass pollens, fungal spores etc.
- Most important allegen for asthma is house dust mites
• Theory of mast cells: located in the submucosa, smooth muscle and adventitia and was previously believed to cause the processes of asthma. However the theory was flawed because it ignored eosinophils and drugs for mast cells had low efficacy.0
- Mast cells in airways has granules in them
- They have high affinity for IgE. Allegens bind and cross link two IgE to activate mast cells.
- Mast cells produce and secrete pre-formed mediators such as histamine and de novo mediators leukotrienes.
- Function of secretions: smooth muscle contraction, mucus secretion and airway wall oedema.
• Function of mast cells in asthma:
- Involved in exercise induced asthma
- Immediate response to allergens
- Cooling and drying of airways
- New theory: when allergen was exposed to mast cells, FEV1 dropped rapidly with IgE activation. Later eosinophils infiltrate and activation in the air produce chronic asthma.
• Involvement of T-lymphocytes: have a central role of increase IgE and eosinophil. There are two types of T-helper cells, TH1 and TH2 (classification of CD4).
- In asthma there is an increase in the no of CD4 T cells but more specifically TH2 cells. These cells produce a cytokine profile that including IL4, IL5 and IL13.
- IL4 and IL13 are associated with increase in IgE production
- IL5 is important in maturation and activation of eosinophils.
- Allergy: in cells affected by allergy, the allergen is presented by dendritic cells to lymph nodes containing CD4 cells and these CD4 cells (namely TH2) migrate into airway.
• Other changes: changes secondary to inflammation can occur, e.g. structural changes of the airways involving epithelial damage, shedding of epithelium. These go away when asthma is controlled.
- Subepithelial fibrosis: increased deposition of collagen deposited underneath the basement membrane
- Increase smooth muscle: hyperplasia and hypertrophy
- Increase in blood vessel of bronchial wall
• Treatment: as inflammation is central to asthma, giving drugs to prevent it is effective to decrease symptoms and airway changes
• Features of asthma:
- Some people are sentitised to the antigen so asthma are mild but with severe cases, asthma tends to be persistent.
- People can develop asthma at any age
- Reversible as inflammation can come and go but a viral infection will make asthma worse.

Lecture 27: Chronic obstructive pulmonary disease

• COPD: disease characterized by progressive airflow limitation that is not fully reversible and associated with an abnormal inflammatory response of lungs to noxious gases.
- Mucus hypersecretion causing luminal obstruction
- Disrupted alveolar attachment
- Mucosal and peribronchial inflammation and fibrosis
• Epidemiology of COPD: 4th leading cause of death
• Risk factors:
- Primarily smoking and particulate exposure
- Alpha 1 anti-trypsin deficiency
- Importance of protease/antiprotease balance in maintenance of lung structure and function
• Elements of COPD:
- Chronic bronchitis: persistent cough with sputum production for at least 3 months in 2 consecutive years, when other causes have been excluded
- Emphysema: permanent increase in the size of air spaces distal to the terminal bronchioles along with destruction of lung parenchyma
- Asthma: inflammatory, reversible airways disease. Chronic poorly controlled asthma leads to irreversibly to lung function testing. Differentiation from asthma by clinical and spirometric features. May need a trial of inhaled steroids to assess presence of asthma
• Reversibility with bronchodilator: COPD has irreversibly damage so application of bronchodilators will not improve FEV1 as significantly as it would for an asthmatic.

(Post FEV1 – Pre FEV1) / Pre FEV1 = % reversibility

• Pathology of COPD:
- Smoking cigarette expose alveolar macrophages with reactive oxygen species causing inflammatory response. Macrophages and neutrophil increase in number and secrete MMP and neutrophil elastase MMP. These proteases digest ECM.
- Antiproteases: AAT (alpha-1 antitrypsin), SLPI (secretory leukocyte protease inhibitor) and TIMP (tissue inhibitor of metalloproteinases) deactivate protease to control matrix degradation.
- Muscle spasm contribute to narrowing of the lung
• Inflammation in COPD: infiltration of large amount of neutrophils, macrophages and T lymphocytes.
• Symptoms of COPD: asymptomatic unless significant decrease in FEV1, i.e. <50%
- Breathlessness: related to increased respiratory effort and hyperinflation
- Decreased exercise tolerance: from deconditioning, and muscle changes
- Increased sputum production: coughs related to increased mucus production by goblet cells, airways inflammation and infection
- Wheeze and exacerbations: signs of airways obstruction
- Late stage: fatigue and weight loss due to increase working of breathing, decrease caloric intake and hypoxia
• Breathlessness in COPD: related to respiratory work or effort but not FEV1. Patient complains of “hard to breathe” and increases respiratory rate and accessory muscle use.
- Increase in work: decrease pO2 and increase pCO2, V/Q mismatch and decrease diffusivity (DLCO) are all respiratory drivers. In addition, obstructed airways, decrease of lung compliance (elastin destroyed), and hyperinflation all contribute to muscle fatigue.
• Diagnosis: onset in later years
- All above symptoms of COPD
- Smoking history (pack years)
- Occupation history (industrial pollution)
- Family history (AAT deficiency etc)
- Exercise capacity (how far they can walk)
• Physical examination: may be normal
- Check for respiratory rate and pattern, e.g. pursed lip to help open airways
- Chest signs such as hyperinflation (AP dimensions) and wheezes during exacerbation
- Can present cyanosis, cachexic (illness health with thinning of body), right heart failure
• Eliminating other diseases: using basic tests such as CXR, full blood count and ECG can help rule out other diseases such as lung cancer, TB, bronchiectasis, TB and left ventricular failure.
- Spirometry analysis: COPD is obstructive pattern so a spirometer result of FEV1 < 70% and FEV1/FVC < 70% (minimal reversibility with bronchodilator) will confirm diagnosis
• Prognosis:
- Smoking cessation is the only intervention that alters lung function decline
- Low body mass associated with increase mortality
- Moderate to severe COPD have average of 3 exacerbations per year
- Increased risk of pneumococcal infection especially in smokers
- Medicine are symptomatic or palliative treatment
• COPD management:
- Reduce risk factors: smoking, occupation exposure and air pollution
- Prevent exacerbation: influenza and pneumoccocal vaccination
- Pulmonary rehabilitation
- Bronchodilators: treat symptoms
• COPD medicine:
- Smoking cessation: nicotine replacement therapy, antidepressant
- Bronchodilators: beta agonists and anticholinergic
- Inhaled steroids: very limited role
- Theophylline
- Long term oxygen only if hypoxic

Lecture 28: Lung Cancer

• Epidemiology of lung cancer:
- Most common cause of cancer death in men and 2nd in women.
- Men incidence increased from 1950’s and peaked in 1990’s but falling
- Increasing incidence in females since 1960’s with no signs of falling (this reflects changes in smoking habits and susceptibility to smoke in females)
- 1956 perspective study of doctors showed clear association
- Risk of lung cancer is higher if co-existing with COPD
• Causation of lung cancer:
- Smoking causes 80% of lung cancer with smokers have 10 times greater risj of death from lung cancer than non-smokers.
- Second hand (environment tobacco smoking) increase risk two folds
- Female susceptibility is possibly due to smaller airways (greater exposure) than men and also genetic factors.
- Further evidence shows risk of lung cancer decrease after cessation of smoking
• Evidence of causality: progression is stepwise with genetic changes
- Experimental: Carcinogens is indentified in tobacco smoke including initiators such as polycyclic hydrocarbons and promoters such as phenol derivatives
- Pathological: histological evidence of a variety of premalignant changes in airways of smokers and normal ciliated cells is replaced by squamous metaplasia that progress to dysplasia carcinoma (in situ to invasive)
• Aetiology:
- Activation of oncogenes: Ras family with k Ras in adenocarinoma and amplification and rearrangement of myc gene leading to loss of transcriptional control. Over-expression of bcl-2 and her-2 are also mechanism.
- Inactivation of tumour suppressor genes: p53 gene (17p13) and Rb – Retinobalastoma gene (13q14). This contributes to over 90% of small cell cancer; p53 loss contribute to over 50% in non-small cell cancer
- Pre-neoplastic lesions: hyperplasia, dysplasia and carcinoma in situ. p53 gene and Ras only involves in carcinoma in situ and invasive disease.
- Multi-step process
- Not clearly Mendelian inheritance with increase risk in first degree relatives
• Non-smokers: adenocarcinoma can occur in non-smokers mostly due to environmental cigarette smoke exposure. Females are more common than males.
• Overall causes of lung cancer:
- Cigarette smoking
- Asbestos: independent carcinogen that is breathed in by miners without mask
- Radon exposure: deep mine
- Occupational carcinogens (arsenic)
- Air pollution
- Scarring: scar carcinoma (fibrosis from tuberculosis produce lung cancer)
- COPD: increase risk
- Sex difference: increase risk in female
• Types of non-small lung cancer: 80%
- Squamous cell 25-40%
- Adenocarcinoma 25-40%
- Large cell 10-15%
- Mixed
• Squamous cell carcinoma:
- Slow growing and prognosis predicted by stage
- Strong association with smoking
- Central mass with endobronchial growth
- Hypercalcaemia from parathyroid hormone produced by cancer
- Cavitation
• Adenocarcinoma:
- Increasing incidence replacing squamous cell carcinoma (possible due to “lighter” smoking)
- Possibly occur for lifelong non-smokers, affecting mostly women and those younger than 45 years old. Because peripheral metastasis is possible, primary lesion should be investigated.
- Broncho-alveolar cancer occurs in peripheral airways and have variable presentation and behavior (looks like pneumonia on X-ray)
• Large cell:
- Peripheral lesion with or without pleural involvement
- Cavitation
- Poorly differentiated and metastasize early
- Poor prognosis tumour
• Small cell lung cancer: 10-20% of all lung cancers
- Strongly associated with smoking
- Often metastasized at presentation
- Small central primary and bulky mediastinal nodes
- Endobronchial spread
- Surgery is never used due to high tendency to metastasize
• Pathway of tumour spread for NSCLC:
- Grows locally and invade contiguous structures
- Spread through local lymph nodes to bronchopulmonary nodes (N1) , then to mediastinal nodes (N2, N3) and distant sites
- Common sites of metastasis include bone, adrenal, liver, brain and lung
• Clinical presentation of NSCLC:
- 10% asymptomatic and picked up by X-ray
- Wheeze occurs usually on one side with obstruction
- Obstructive pneumonitis: pneumonia usually cleared in 6 weeks but if not, it can progress to completely further obstruct distal airways
- Haemoptysis
- Cough
• Further clinical signs: tumour at apex of lung
- Dysphagia: pressure on oesophagus
- Hoarseness: recurrent laryngeal nerve compression
- Dyspnoea
- Horner’s syndrome (compression of sympathetic chain)
- SVC obstruction
- Pericardial tamponade
- Chest pain
• Diagnosis:
- History of smoking, family relations, symptoms such as cough and haemoptysis
- Examination finds prescience of clubbing (no notch/angle of the nail), obstruction of airways and SVC and pleural effusion consequently
• Investigations:
- Diagnostic tests: chest X-ray, sputum cytology, bronchoscopy, CT guided FNA
- Staging test: CT staging (show spread of cancer) and blood levels
• Treatment for NSCLC:
- Early stage disease (stage I and II) is surgery such as lobectomy or pneumonectomy
- Locally advanced disease (stage III) has surgery combined with radio/chemotherapy
- Advanced stage (stage IV) is chemotherapy for fit patients
• Treatment of small cell carcinoma: treatment is chemotherapy for advanced disease
• Prognosis:
- NSCLC: 5 year survival is above 40% with operable tumours. Only 10-15% operated on so majority of treatment is palliative
- SCLC: limited disease with 5-10% survival for 3 years.

Lecture 29: Airway Pathology

• COPD:
- Associated with ageing, occupational exposure (coal mining) and AAT deficiency
- Decline in lung function is very slow (faster when older)
- Asymptomatic at first as the body adapts
- Differentiation: patients can lose weight, increase work of breathing and maintain oxygenation while others are hypoxic, overweight and no increase in respiration.
• Chronic bronchitis:
- Associated with mucus gland hyperplasia and hypertrophy
- Not all have airflow obstruction
• Emphysema:
- Damage airways with destruction of septae (some are thickened)
- More likely to be in upper lung than lower lung.
- Decrease expiratory flow rate due to decrease elastic recoil of alveolar wall through damage to alveoli. Also increase in narrowing of airways increase resistance
• COPD severity:
- In mild COPD, there is increase in CD8 T cells and macrophages with reinforcement by helper T cells
- In severe COPD increase in neutrophils is more than normal
• Airway damage: in small airways, there is loss of alveolar attachment (ligaments that anchor alveolar to surrounding small airways).
- Elastin decrease in small airway have more effect in narrowing than fibrosis
• Premature closure of airway: increased residue volume and decreased total lung capacity causing the RV/TLC ratio to increase.
- For asthma, this is reversible but in COPD they are chronically hyperinflated.
• Alpha-1-antitrypsin deficiency: genetic mutation causing early onset of COPD.
- Smokers with emphysema suffer centriacinar emphysema with only middle of acinus affected but those with deficiency have whole acinus affected.
- This enzyme inhibit the action of elastase released by neutrophils
• Pulmonary hypertension: right hear failure due to hypoxia causing bronchoconstriction.
• Bronchiectasis: permanent dilation of bronchi with cough and chronic sputum production (chronic bronchitis lack dilation)
- Symptoms: haemophysis, breathless, and wheezing
- Can suffer chronic infection in severe cases
- Striking loss of elastic fibers, infiltration by neutrophils, lymphocytes and scarring
- Severe bronchiectasis is irreversible
• Vicious cycle: impaired mucocillary clearance lead to reduced secretion and high risk of infection. This will leads to tissue damage and further impair mucocillary clearance.

Lecture 34: Occupational Lung Disease

• Importance of breathing through nose: warms and filters the air component so reduce effect of pollutants
• Pneumoconiosis: pulmonary disease caused by the inhalation of inorganic dusts from occupational pollution
- Silicosis
- Asbestosis
- talcosis
• Features of pneumoconiosis:
- History hard to obtain due to patient ignorance
- Often masked by the effect of smoking
• Asbestosis: diffuse lung fibrosis caused by the substance asbestos. This mineral consists of a group of fibrous silicate in the form of long thin fibers.
- Type of asbestos: chrysolite (blue asbestos) have curvy fibers while crocidolite have long thin fibers (white asbestos)
- Asbestos is used commonly for ceiling so during ripping out ceiling, fibers dust can be breathed in and cause potential harm.
• Pathogenesis: long thin asbestos fibers are deposit in the airways and alveoli particular at bifurcation of alveolar duct. Small fibers are engulfed by macrophages but larger fibers penetrate into the interstitial space.
- Asbestos fibers does not get broken down in the lung
- First pathology is alveolitis where inflammatory mediators by macrophages and this with the fibers promote interstitial fibrosis
- Cancer: fibers are a physical carcinogen. Within a cell, it prevents mitotic separation and produce in a binucleate cell. Such cells will divide abnormally forming cancerous cell.
- Other effects: other organs such as bladder and oesophagus can also contract cancer from asbestos
• Honey-comb appearance: shown on chest X-rays and CT scans predominantly in the lower lobes.
• Benign pleural effusion: must fit four criteria
- History of asbestos exposure (occurs within 10 years)
- Identification of a pleural effusion
- Absence of other disease
- No malignant tumour
• Pleural plaques: occurs in parietal and diaphragmatic pleura (10-20 years after exposure)
• Rounded atelectasis: pleural fibrosis and adhesion produce atelectasis which has a rounded appearance on chest X-ray and CT scan.

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