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Question 1

List non-neoplastic and neoplastic lesions of lung

Answer 1

NON-NEOPLASTIC
Congenital: congenital pulmonary airway malformation …
Infection: Pneumonia, Abscess
Inflammation: TB granuloma
Deposits: haemochromatosis

NEOPLASTIC
Benign: Hamartoma, Hemangioma, Adenoma
Malignant:
1. Small Cell Lung Cancer
2. Non-Small Cell Lung Cancer:
adenocarcinoma
squamous cell lung cancer
large cell lung cancer
3. Secondary metastasis

Question 2

Describe malignant neoplasms of lung

Answer 2

NEOPLASTIC - Malignant
1. Small Cell Lung Cancer 15%
2. Non-Small Cell Lung Cancer 85%
adenocarcinoma 35-40%
squamous cell lung cancer 25-30%
large cell lung cancer 10-15%

Risk Factor =Smoking, Family Hx, Occupational Exposures, gene mutations (p53), other cancers

Question 3

Describe sclc

Answer 3

associations
Neuroendocrine tumor (NET) 🡪 Lambert Eaton Syndrome, ACTH production & Cushing’s syndrome
pathology
Centrally located, histologically; minimal cytoplasm with hyperchromatic cells
treatment/prognosis
Rapid growth, early dissemination often at presentation

Question 4

Describe squamous celll lung cancer

Answer 4

associations
Most common lung cancer, smoking correlation +++,
pathology
Centrally located, hilar region & major bronchi, histology = keratin pearl, intercellular bridges, bronchial mucosa is not usually squamous epithelium metaplasia 🡪 dysplasia
treatment/prognosis
Local or distant metastasis, may cavitate

Question 5

Describe adenocarcinoma

Answer 5

associations
Non-smokers, demographics: ?younger, female,
pathology
Peripherally located, Histology = glandular, mucin producing
treatment/prognosis
Early and distant metastasis
EGFR inhibitors for treatment potentially appropriate

Question 6

Describe large cell lung ncancer

Answer 6

associations
Diffuse and undifferentiated, anaplastic
pathology
Peripherally located, Histology = giant cells, spindle cells
treatment/prognosis
Metastasis early and distant

Question 7

Describe treatment for lung cancer

Answer 7

Depends on
Type, grade (down the microscope), stage (TNM)
Background lung tissue
Surgery 🡪 +/- Chemotherapy, Radiation

Clinical signs:
Pancoast Tumour = compression of the sympathetic chain at the apex of the lung, causing Horner’s syndrome (Ptosis– drooping eyelid, Miosis – pupil constriction, Facial anhidrosis – absence of sweating)

Question 8

Define diffusion and describe the determinants

Answer 8

Diffusion:
Gas exchange taking place at the blood-air barrier.
Blood air barrier constituents:
Type 1 pneumocyte
Basal lamina
Endothelial cell
Determined by Fick’s Law

Diffusion issues = gas exchange issues

Question 9

Describe ventilation and issues of ventilation

Answer 9

Ventilation:
Effectiveness of the respiratory pump
Constituents:
Chest wall (ribs, respiratory muscles*)
Lung (parenchyma and pleura)
Ventilation issues = pump failure
NOT gas exchange issues
This is why a ventilator is an external pump that pumps air into the patient who is still capable of gas exchange.
Ventilation issues causes hypercapnia = Type 2 respiratory failures
Cf. diffusion issues causes hypoxia = Type 1 respiratory failure

Question 10

Describe perfusion and issues of perfusion

Answer 10

Perfusion:
Supply of blood to the lung
Important as blood carries the main gases exchanged: O2 and CO2

Perfusion issue = blood (and gas) delivery issues
NOT gas exchange NOR pump issues.

Question 11

Describe the balance of pressure that keeps the lung open/describe pressure, volume and flow changes in respiration

Answer 11

Inspiration
- typically the chest wall and lungs and brought together to form a single unit
- in inspiration, these layers separate
- as a result, intrapleural pressure becomes more negative, as the visceral layer and lung expand, following chest wall expansion
- this trend towards increased negativity can be seen on the graph
- during this time, alveoli becomes more negative
- however as air enters, the alveolar pressure approaches atmospheric pressure as it becomes more open and continuous with the air, and air is sucked in so that pressure equalises
- at this point, when pressures equilibrate, there is no more movement of air (net?)

In expiration:
- the parietal pleura approaches the visceral pleura
- as a result, the intrapleural pressure is less negative
- the lung decreases in size
- positive pressure within the alveoli pushes air out, brings back alveolar pressure to bormal
- at this point, when pressures equilibrate, there is no more movement of air

Flow and Ohm’s Law:
- Flow is the amount of a substance passing a point per unit time
- It can be thought of as volume over time
- Flow within the body is analogous to flow in an electrical current and is governed by Ohm’s law: Resistance = Potential/Current
- In the body, this becomes Flow = Pressure difference/Resistance

Note that the graph of air flow matches the alveolar pressure change graph. This illustrates that the flow is proportional to the pressure gradient in the alveoli, assuming resistance is unchanged.

Note also that the intrapleural pressure is negative or subatmospheric because - the tendency has a tendency to recoil and the chest wall has a tendency to expand.

Question 12

Describe FRC

Answer 12

• The amount of gas remaining in the lung after tidal expiration
• FRC is the point where the balance between the tendency of the chest wall to spring outwards and the tendency of the lungs to collapse inward is equal
• FRC is reached when in- and expiratory muscles are “relaxed”
• Functions of FRC: minimizes work of breathing (requires less inflaton and therefore less energy expenditure), pulmonary vascular resistance, V/Q mismatch (?), airway resistance, primary oxygen store, prevents atelectasis (failure of part of the lung to expand), prevents collapse, and provides buffer to maintain steady arterial pO2
• this last point is especially important
• without FRC there would be blood not supplied with oxygen during expiration

Question 13

Descrive FV loops

Answer 13

Flow Volume Relationship:
- Flow-volume loops provide graphical representation of patient’s respiratory effort and help classify disease
- Maximal efforts required for indicative curves (training)
- Positive flow: expiration, negative flow: inspiration
- Information from FV loops: FVC, TLC, PEF, MEF, MIF
- Clinically more important to understand the value of numbers in different diseases than the numbers themselves
- FEF25 i.e. 25% of TLC expired
- note again PEF is early
- note MEF is very sensitive to OLD due to obstruction in small airways (?)

Obstructive and Restrictive Disease:
- Obstructive disease: Small airways disease leads:
- to gas trapping
- increased resistance to airflow, increased RV and TLC (air trapped)
- decreased FVC and FEV1
- decreased FEV1/FVC ratio
- decreased MEF
- left shift of curve, indicating higher TLC, and slower downward slope (coving?)
- note PIF also decreased, though not a s dramatic as PEF
- Restrictive disease: Scarring within airways leads to:
- decreased lung compliance
- fall in TLC, FEV1, FVC
- normal or slightly increased FEV1/FVC ratio, in other words, largely unaffected
- right shift of curve, shrunken loop, but shape retained

Question 14

Describe work of breathing

Answer 14

Work of Breathing (PV Curve):
- Work = Force x Distance
- In the respiratory system, Work = Pressure x Volume
- Three main types of work of breathing:
- Inspiratory - Elastic and non-elastic work
- Expiratory work

Elastic work:
- 65% of work
- compliance work, to overcome recoil of the lungs
- work against elastic forces stored as potential energy which is used during expiration
- any factor that decreases compliance will increase elastic work

Non-elastic work
- remainder: 35% of work
- work to overcome airway resistance
- non-elastic work lost as heat
- any factor that increases resistance will increase non-elastic work

Expiratory work

• This is the work required to overcome airway resistance during expiration
• it is the same as non-elastic work, in terms of energy requirements
• in normal breathing, this is easily accounted for by the potential energy stored during elastic work
• if airway resistance increases significantly through more energy will be required (recruiting expiratory muscles) and expiration becomes an active process

Question 15

Describe the controls of respiration

Answer 15

Sensors:
Central chemoreceptors – samples H+ in CSF (so CO2 indirectly)
ONLY detects CO2
Peripheral chemoreceptors – carotid bodies (NOT SINUS*) + aortic arch
Detects O2 and CO2
Others:
Lung receptors
Baroreceptors
Muscle/Joint receptors

Goal: Detect changes in CO2 and O2, and report (increase nerve firing) to the controllers.

Controller

• Medullary Respiratory Center, which is comprised of:
  
  • VRG/DRG: Ventral and Dorsal Respiratory Group.
  • Pre-Botzinger Complex – The Pacemaker

The central pattern generator is located within the medulla.

It receives many sources of input, including:
- hypothalamus (limbic, related to emotion, triggers autonomic system response)
- pons
- cortex (voluntary control largely)
- chemoreceptors
- other reflexes

In turn, the central pattern generator outputs to either stimulate inspiration or expiration.
The CPG also sends signals to inspiratory and expiratory motor neuron pools.
- expiratory signal inhibits inspiratory motor neuron pool

Groups of nuclei include the dorsal respiratory group, which is associated with inspiration, and the ventral group, which is mixed with inspiratory and expiratory signalling. It is associated with the timing of the respiratory cycle.

Recall from [[Physiology B2 - Lecture 19]] there are multiple nuclei associated with stages of respiration, and fire at different frequencies:
- early inspiratory
- augmenting etc

Sensors:
There are threee sensors: central and peripheral chemoreceptors, and mechanoreceptors

• Central Chemoreceptors
  
  • located within the medulla
  • as they are CNS structures, they are enveloped by meninges
  • in other words, there is a blood-brain barrier
  • H+ cannot diffuse across
  • CO2 can
  • it reacts with water to form H2CO3, which dissociates to form HCO3- and H+
  • H+ then interacts with chemoreceptors
  • if there is high pCO2 in the blood, more H+ is detected, which increases firing and stimulates the CPG to increase respiratory rate

Note: the chemoreceptors have a low tolerance to pH changes in CSF. It is buffered bicarbonate shift to normalise pH and reset chemoreceptor sensitivity.

Note 2: mechanism of bicarbonate shift debated

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Note 3: ventilation changes with PaCO2 - reflects differing sensitivities of chemoreceptors.

If left shifted, the threshold is changed. Earlier response, steeper slope. Fast respiratory rate.

When right shifted, slower response, and less steep slope.
Slower respiratory rate.

Note that PaCO2 increases with minute ventilation.
Hypoxaemia produces a steep slope.
High PaO2, decreases response to CO2.

• Peripheral Chemoreceptors
  
  • responds to more i.e. H+, CO2, O2
  • note: it responds to dissolved O2 NOT O2-Hb
  • peripheral chemoreceptors are the first to respond to pCO2 changes, although central chemoreceptors do most of the heavy lifting (80%)
  • peripheral chemoreceptors are heavily perfused, which means changes to cardiac output affect detection
  • three cells present at peripheral chemoreceptors
    
    • type I Glmous cells: have oxygen sensitive potassium channels, which close if pO2 decreases, thus increasing pCO2 sensitivity
      
      • CO2 sensitivity increased by hypoxia < 60mmHg
    • type II: maintain homeostasis

Note: peripheral chemoreceptors are sensitive to acid. Decreasing pH increases minute ventilation and vice versa.

Pulmonary Mechanoreceptors:
- Essentially stretch receptors in trachea and bronchi
- Inflation reflex, most present in neonates, prevents overinflation/overdistension and increases desire to breathe out
- Hering-Breuer reflex aka

Question 16

Describe the dynamic nature of the FV loop

Answer 16

Work = Pressure x Volume = Area in loop
Compliance = Δ Volume / Δ Pressure
Aka ‘compliance curve’ or ‘work curve’
ABCD0A = Total work during inspiration
AECD0A = Elastic work (65% of work) to open alveoli
Also called compliance work, decreased compliance = decreased Δ volume/ pressure = flatter curve = more area = more work
ABCEA = Non-elastic work (35% of work) to open airways
Also called resistive work, increase resistance = more work
AECD0A = expiratory work
Usually passive as it uses energy stored during elastic work, in pathology can require active work – e.g. COPD

Question 17

Describe changes to breathing work in disease

Answer 17

The amount of work required dictates our respiratory rate.
Elastic work = compliance work = alveolus opening work
Faster RR = alveolus doesn’t collapse completely between breath = less work needed to re-open.
Non-elastic work = resistive work = airway opening work
Faster RR = faster air flow causes turbulence = more work to keep air flowing
In a healthy individual the body finds the optimal RR where both are lowest = 15 breath per min

Obstructive disease = small airway problems
Small airways = airflow/non-elastic work
Air-flow curve dominates = RR decrease to minimize air flow work
New optimal total established at lower RR
Patient with obstructive diseases breaths slow and deep
Restrictive disease = alveolus problems
Alveolus = elastic/compliance work
Elastic curve dominates = RR increases to minimize elastic work
Patient with restrictive diseases breaths fast and shallow

Question 18

Describe V/Q mismatches

Answer 18

V = Ventilation
Q = Perfusion
V/Q = 0 means no ventilation, means a shunt
Shunt = perfused but not in a ventilated area
Causes can be physiological (bronchial veins, Thesbian veins) or pathological (pneumonia, atelectasis)
Results in venous admixture
V/Q = ∞ means no perfusion, means dead space.
Dead space = ventilated but not perfused areas
Anatomical dead space: gas within conducting airways
Alveolar dead space: gas in alveoli that doesn’t participate in gas exchange
Physiological dead space = alveolar + anatomical dead space
In pathology alveolar dead space increases e.g. PE
In lung lobes there is a gradient of V/Q between these extremes.

Gradient in lung in terms of V/Q in an upright patient*
Flow and ventilation both highest at base of lung but low V/Q ratio (~0.6)
Closer to shunt

Flow and ventilation lowest in apex of lung but high V/Q (~3.2)
Closer to dead space

V/Q perfectly matched at around the 3rd rib

Question 19

Describe changes to lung in acidosis and alkalosis

Answer 19

Act as a pH buffer to excrete acids (in the form of CO2)
Tightly maintains the 20:1 ratio of HCO3-:CO2 (base: acid)
Ratio matters more than amount, hence if the ratio is right then the kidney can take its time making bicarbs.
Hyperventilate to blow off more CO2 to increase pH.
Does not hypoventilate to correct alkalosis cause O2 matters more

Question 20

Describe DLCO

Answer 20

Gas transfer TlCO or Diffusing capacity DlCO

• Transfer or diffusion of CO (carbon monoxide) across the lung in a single breath manoeuvre (2 step process)
  
  • Rate of uptake of CO (ml/min) divided by the driving pressure (mm/Hg)
  • The alveolar volume (VA) – accessible lung volume seen by the gas exchange surface (participating in gas exchange)
• Total diffusing capacity of the whole lung = diffusing of the pulmonary membrane component plus capacity of the pulmonary capillary blood volume

Gas transfer techniques
Test performance
- Patient exhales to residual volume
- Maximal inspiration to TLC during which a volume of test gas is inhaled
- The test gas is held in the lungs for approximately 10 seconds
- A portion of exhaled air/gas mix is discarded to wash out the mechanical and anatomical dead space not associated with gas transfer
- A portion of exhaled alveolar volume is analysed to calculate the TLCO and VA

Interpretation of gas transfer
Comparison of TLCO against LLN and severity based on %predicted
* > 60% and < LLN : Mild gas transfer impairment
* > 40% and < 60%: Moderate
* < 40%: Severe

Consider correction for haemoglobin and Carboxyhaemoglobin

Increase in TLCO > ULN, but remember this can still be normal!

Serial Change (Trend)
- TLCO change > ± 4.78mmol/min/mmHg in 1 week is considered to be significant
- 10% change over 1 year is considered to be significant for TLCO

Decreases in TlCO occur in:
- emphysema and reduction in alveolar surface area
- anemia, due to reduced haemoglobin and elevated CO-Hb
- PE due to reduction in capillary blood volume
- Fibrosis or pneumonitis due to increased thickness of alveolar membrane
- Volume loss pneumonectomy or atelectasis due to reduction in alveolar membrane SA

Note: Valsalva Manoeuvre – increase in positive pressure decreases pulmonary capillary blood volume in thoracic cavity

Note 2: changes in gas composition in lung: PIO2

Obstructive Lung Disease
 Emphysema (decreased surface area)
 Cystic Fibrosis (increased thickness of alveolar – capillary membrane)

Parenchymal Lung Diseases (increased thickness of alveolar – capillary membrane)
 Interstitial lung disease
 Idiopathic
 Sarcoidosis
 Asbestosis

Pulmonary involvement in Systemic Diseases (increased thickness of alveolar – capillary membrane)
 Systemic lupus erythematosus
 Rheumatoid arthritis
 Scleroderma
 Wegener’s granulomatosis

Anaemia

But also,

Cardiovascular diseases
 Acute and recurrent pulmonary thromboembolism (decreased perfusion surface area)
 Pulmonary oedema (increased thickness of alveolar-capillary membrane)
 Pulmonary Hypertension (decreased capillary volume)

Lung resection
- Pneumonectomy (decreased surface area)

Other
 Cigarette smoking prior to testing
 Marijuana
 Pregnancy
 Oxygen supplementation
 Valsalva manoeuvre

Increases occur in
* Low PIO2 due to altitude: due to changes in gas composition in lung
* Exercise, redistribution of blood flow due to pneumonectomy, Mueller manoeuvre: due to increase in capillary blood flow
* Impaired gas exchange: due to polycytehamia
* Pulmonary haemorrhage: blood in alveolar spaces
* Supine Posture

Question 21

Describe 6mwt

Answer 21

Exercise testing - functional assessment
6 Minute Walk Test
 Measure of overall physical functioning and prognosis
 Measures walk distance, oximetry & dyspnoea perception
 Responsive to change
 Less technical equipment needed
 Standards needed to minimise variability

Clinical Utility in pre and post treatment including:
 Lung transplantation
 Lung resection
 Lung volume reduction surgery
 Pulmonary rehabilitation in COPD and Congestive Heart failure
 Therapeutic response for Pulmonary Arterial Hypertension

Cardio-pulmonary
 Test of integrated function under stressful conditions using increasing workload
 Measures:
 Ventilatory parameters
 Cardiac parameters including ECG
 Metabolic parameters
 Determine underlying course of dyspnoea or reduced exercise tolerance; e.g. lungs, heart, vascular, perception
 Can be used to monitor treatment
 Resource intensive

Question 22

Describe body plethysmography

Answer 22

Body plethysmography
- Tidal breathing is determined at FRC, a shutter is closed and the patient gently inhales and exhales (pants) against the closed shutter for 3 seconds
- The expansion and decompression of the air in the lungs causes small volume (change in box volume) and pressure changes in both the lungs and the body plethysmograph
- FRC is derived using Boyles Law (P1.V1 = P2.V2) from mouth pressure (change in alveolar pressure) and box pressure
- IC and VC are measured, to derive TLC and RV respectively

Interpretation of Lung Volumes
- Comparison of TLC against LLN and cut-off: severity based on % predicted.
- < LLN and 70% of predicted: Mild restrictive ventilatory defect
- < 70% and > or = to 60%: Moderate
- < 60% and > or = to 50%: Severe
- TLC > upper limit of normal may indicate lung hyperinflation.
- Consider larger than expected lung subdivisions in interpretation.

• Air trapping defined as disproportionate increase in residual volume (RV) or RV/TLC ratio.
  
  • RV/TLC ratio of > 120%: Mild air trapping
  • RV/TLC ratio of > 140%: Moderate
  • RV/TLC ratio of > 160%: Severe

Question 23

Compare and contrast type 1 and 2 repiratory failure

Answer 23

Types of Respiratory Failure
- Type 1: Hypoxaemic respiratory failure
- Arterial partial pressure of oxygen (PaO2) ≤ 60mmHg on room air.
- Type 2: Hypercapneic respiratory failure
- Arterial partial pressure of carbon dioxide (PaCO2) ≥ 45mmHg.

Clinical Signs of Respiratory Failure
- Paradoxical breathing ^[obstruction leads to see-saw of chest and abdominal movements on inspiration] due to ineffective ventilation
- Increased sympathetic tone= tachycardia, hypertension and sweating
- **Clinical signs of respiratory compensation:
- Tachypnoea.
- stridor or wheezing
- Use of accessory muscles.
- Nasal flaring.
- Intercostal, suprasternal, or supraclavicular recession.

Clinical Signs of Respiratory Failure (cont.)
- End-organ hypoxia:
- Altered mental status.
- Bradycardia and hypotension (late signs).
- Haemoglobin desaturation:
- Cyanosis.

Question 24

HIHIIHI

Describe transport and distribution of O2 and CO2

Answer 24

Oxygen Carriage

• Forms of Oxygen Carriage
  
  • Dissolved in Solution: Limited due to low solubility (per Henry’s L); 15ml of O2 dissolved in 5L blood
  • Bound to Haemoglobin: O2 binds to iron in haem; 1.39ml ^[calcd with Huffner’s c] of O2 per g of Hb (in vivo ~1.34ml due to Hb types e.g metHb)
• Haemoglobin States:
  
  • Relaxed (binds O2 easily): R state - favoured in alkalosis, hypocapnoea, hypothermia, decreased 23DPG
  • Tense (unloads O2 easily): T state – inverse ^[e.g. fetal, no beta subunit]
  • PHENOMENON = Bohr effect: alteration in O2 binding capacity of Hb depends on surrounding environment ^[a.k.a how readily]
  • Binding of one O2 favours Hb R state–‘more can bind more easily’: sigmoid shape ^[mind ICU point - 60 mmHg]
• Oxygen Delivery (DO2):
• CO x Arterial oxygen carrying capacity
  
  • DO2 = (HR x SV) x ((1.34 x Hb x SaO2) + (PaO2 x 0.0?3)) ^[how much bound, how much dissolved]
  • DO2 = 1000ml/min (rest) (e.g. - assuming all good)
• Oxygen Consumption: Rest ~250ml/min; mixed venous oxygen saturation 75%
  
  • changes with metabolic demand

CO2 Carriage

• Forms of CO2 Carriage
  
  • Dissolved in Solution: More soluble than O2; 5% of CO2 carriage, 10% of AV difference
  • Bicarbonate: CO2 + H2O → H2CO3 → H+ + HCO3- ^[CA influence]; 90% of CO2 carriage, 60% of AV difference
    
    • H+ - buffered by Hb
    • HCO3 swapped Cl (Chloride shift)
  • Carbamino Compounds: CO2 combines with terminal amino groups on proteins, Hb most important here (most abundant protein in red cell); **5% of CO2 carriage, 30% of AV difference
• Haldane Effect:
  
  • Deoxygenated blood transports CO2 more effectively (70% via carbamino compounds, 30% via buffering H+ - Hb free to buffer)

O2 and CO2 exchange in pulmonary capillaries
The capillary wall is permeable to CO2 and O2.
O2 diffuses across wall into red blood well. It displaces proton binding to Hb.
Proton participates in CA reaction, dissociates to CO2 and H2O. CO2 diffuses out.
Note carbaminohaemoglobin, which dissociates.
Reverse chloride shift: Cl out and HCO3 in

O2 and CO2 exchange in systemic capillaries
The reverse process occurs in systemic capillaries.

The capillary wall is permeable to CO2 and O2.
CO2 diffuses across wall into red blood well. It displaces proton binding to Hb.It also participates in CA reaction, dissociates H+ and HCO3. H displaces O2 from Hb, O2 diffuses out
Note oxygenated haemoglobin, which dissociates and takes up CO2.

chloride shift: Cl in and HCO3 out

CO2 transport in blood
In the red cell:
- 63% CA reaction
- 21% Hb
- 5% dissolved

In plasma:
- 1% Hb
- 5% CA reaction ^[slow reaction]
- 5% dissolved

Question 25

Compare and contrast obstructive and restrictive disease

Answer 25

Pathophys

OBSTRUCTIVE: Airflow problem
Roughly: Harder for air to get out of the
lungs, which can be for a few reasons
1. Asthma - bronchoconstriction
2. COPD:
a. Emphysema - decreased elastic recoil,
air trapping, airway collapse
b. Chronic bronchitis - increased
secretions, airway narrows
3. Bronchiectasis/CF - increased
secretions, airway narrows

RESTRICTIVE: Lung expansion problem
Roughly: Can’t really breathe too deeply. If
chronic, mostly due to scarring of lungs from
genetic, autoimmune, environmental or
idiopathic reasons.
Upper lobe fibrosis: SSTARCH (Silicosis,
sarcoidosis, TB, aspergillosis, radiation, coal
worker’s lung, histiocytosis)
Lower lobe fibrosis: RASCO (Rheumatoid
arthritis, asbestosis, scleroderma,
cryptococcus, other - drugs eg
methotrexate)

Normally abnormal expiratory
breath sounds eg expiratory wheeze

Normally abnormal inspiratory
breath sounds eg inspiratory crackles

 Cough
 Very varied, characterise sputum colour
 Can be purulent in exacerbations
 Dry cough -> Consider pulmonary fibrosis
 Chronic purulent cough -> Think bronchiectasis, consider CF
 Dyspnoea (Shortness of breath)
 Wheezing → more likely asthma
 Good social Hx about smoking, occupation and environmental
exposures is super valuable. Don’t forget FHx of asthma, lung
cancer, etc.

Question 26

Describe investigations to distinguish between obstructive and restrictive disease

Answer 26

• spiromtery
• body plethysmography
• iamging
• ## bronchodilator test

Question 27

Describe the stages of bacterial pneumonia

Answer 27

If lobar,
- Morphologic changes in the lung tend to follow a classic sequence.
- Four stages:
- Congestion
- Red hepatisation
- Grey hepatisation
- Resolution
- Since the introduction of antibiotics, this sequence is often altered.

Congestion
- Enlarged lobe.
- Heavy and congested with blood.
- Blood-stained fluid from the cut surface.
- Dilated alveolar capillaries.
- Air spaces filled with pale fluid.
- Scattered red blood cells and neutrophils.
- Occasional bacteria.

Red Hepatisation
- Cut surface is dry and red.
- Resembles liver macroscopically.
- Fluid containing fibrinogen has clotted in alveolar spaces.
- Increased numbers of neutrophils.
- Bacteria more numerous.

Grey Hepatisation
- After 2-3 days, loss of the red color.
- Starts at the hilum and moves out.

• Migration of large numbers of neutrophils.
• Decrease in capillary congestion.
• Virtual cessation of blood flow through the unventilated lobe.

Resolution

• Liquefaction of the previously solid exudate.
• Fibrinolytic enzymes.
• Apoptosis of neutrophils.
• Fluid contents removed:
  
  • Expectoration
  • Lymphatics.
• Takes several weeks.

Question 28

List pathologies of restrictive diseases

Answer 28

e.g. ARDS
- capillary endothelial and alveolar damage
- release of cytokines and interleukins, which in turn
- activation of neutrophils (release proteases, oxidants), which migrate into interstitium–>oedema, thickened interstitium due to infiltrate
- increased vascular permeability
- exudation of fluid- alveolar flooding
End-result is decreased diffusion
Macroscopy: heavy, boggy, oedematous and red lungs

CRPD:
similar to acute

• different mechanisms leading to inflammation ofo alveoli
• accumulation of inflammatory cells in the alveolar walls and spaces
• release of mediators e..g cytokines and interleukins
• alveolar wall damage
• ## fibrosis of the alveolar walls (irreversible and poor prognosis)

Usual interstitial pneumonitis ^[c/c]
- Repeated sequential cycles of acute lung injury- alveolitis leads to progressive fibrosis (Wound healing with fibroblastic proliferation)
- Early stages: fibroblastic proliferation/fresh fibrosis/fibroblast foci
- Late: collagenous, acellular scarred areas/pld

Both early and late stages are seen together:
- temporal heterogeneity: presence of both fresh and old fibrosis
- regional heterogeneity (areas of relative sparing)
-
### Non specific interstitial
Diagnosis is one of exclusion, as many other diseases mimic this.
Characterised by:
- Interstitial lymphocytes and plasma cells, interstitial thickening
- Diffuse or patchy interstitial fibrosis (temporally homogenous, all old, uniform appearance)
- variably cellular (inflammatory) and
- Absence of fibroblastic proliferation (all old fibrosis)
-
Asbestos
* Pleural plaques: fibrosis in parietal and visceral pleura
* Diffuse pulmonary fibrosis (Asbestosis)
* Recurrent Pleural effusions
Note: usually colourless, but if iron deposits, can see (ferrogenous bodies)
-
Carbon and silica

– Initial formation of nodules in the upper lobes of the
lung: fibrous scars, “hard”
- found in lymph nodes, parenchyma and pleura
* Nodules contain dust particle, macrophages and delicate network of collagen
* Macrophages secrete mediators: attract lymphocytes, fibroblasts
* Cause damage to alveolar cells and interstitium
– Disease progression leads to formation of hard
collagenous scars
– Scars may often be pigmented in coal workers
-
## Granulomatous lung diseases
Hypersensitivity pneumonitis (extrinsic allergic alveolitis): reaction to inhaled organic antigens or chemicals: e.g farmers lung, Bird-fanciers lung, hot-tub lung ^[type 4?]
- Some antigens are actually infectious agents
Features:
- nodular
- multi-nucleated giant cells
- macrophages
- surrounded by lymphocytes

^not an exhaustive list

Question 29

Describe the histology of asthma

Answer 29

Acute Response

• In sensitized individuals
• Exposure of the airways to specific allergens results in crosslinking of IgE present on the surface of mast cells and triggers the release of inflammatory mediators
• Increased vascular permeability
• Bronchial smooth muscle contraction
• Increased mucous secretion.
• Allergic airway phenotype results from cytokine production from T cells as well as from inflammatory mediators released from recruited eosinophils and other cells in the lung.
• Mucous hypersecretion
• Smooth muscle cell hyperreactivity
• Airway remodeling with chronic inflammation.

Chronic Response

• Influx of inflammatory cells
• Th2 cells, eosinophils
• Cytokines produced by both eosinophils and T cells promote the homing of eosinophils to the site of inflammation followed by differentiation, activation and degranulation
• Cycle of ongoing tissue injury
• Increase in inflammatory infiltrate
• Chronic inflammation - perpetuated by both cytokines and the products released by eosinophils
• Increasing evidence that other subsets of CD4+ T cells play a role in orchestrating inflammatory changes
• Th1, Th17, Treg, CD1d restricted NKT cells, TFH

Gross description
* Overdistended lungs, small areas of atelectasis, thick mucus plugs in proximal bronchi containing whorls of shed epithelium
Microscopic (histologic) description
* Curschmann spirals, eosinophils, extracellular Charcot-Leyden crystals (crystalloids composed of galectin-10, an eosinophil lysophopholipase), increased mucosal goblet cells and submucosal glands, thickened basement membrane, bronchial smooth muscle hypertrophy, airway wall edema

Question 30

Describe the pathophysiology of asthma

Answer 30

There are two factors that contribute to the development of asthma.
These include changes to the airway walls and lumen.
The airway walls become infiltrated with mononuclear cells, especially CD4+ T cells and eosinophils.
Severe asthma is associated with increasing neutrophil infiltration. This is because, as asthma progresses, there are increased numbers of degranulated mast cells, macrophages, plasma cells and neutrophils found in the airway walls.

Changes within the airway lumen include increased secretions, containing lymphocytes, activated macrophages, eosinophils and epithelial cells.

With inflammation comes remodelling of the airway.
This involves cellular and molecular changes to the airway, affecting its structure.
Changes include:
- epithelial injury
- subepithelial thickening and fibrosis
- airway smooth muscle cell hyperplasia. This in particular affects recruitment of inflammatory cells.
- goblet hypertrophy and hyperplasia
- angiogenesis

These structural changes contribute to

• bronchial hyper-responsiveness which is correlated with inflammation, and is influenced by diameter of lumen, muscle contractility, epithelial injury, neuronal deregulation and microvascular permeability, airway obstruction, and associated symptoms characteristic of asthma including breathlessness, wheezing and coughing
• Airway obstruction which is characterised as increased airway smooth muscle mass, increased matrix protein deposition, disruption of surfactant function, and excess mucous with extravasated proteins and inflammatory cells comprising plugs.

also TGFb

Question 31

Interpret spirometry

Answer 31

Spirometry Interpretation**
- Use FEV1/FVC ratio to detect obstruction.
- Use FEV1 as % predicted to grade obstruction severity.
- Use **FVC to assess restriction:
- low FVC or VC in presence of significant obstruction does not necessarily indicate restriction
- **confirm and quantify with Total Lung Capacity measurement in respiratory lab
- Bronchodilator reversibility: Significant reversibility is a ≥12% improvement in FEV1 (FVC) and an increase of at least 200 ml after bronchodilator therapy.

Question 32

Distinguish between respiratory acidosis and alkalosis

Answer 32

Respiratory
- A result of abnormal Pco2
- if elevated = acidosis. If low = alkalosis. Compensated with metabolic alkalosis and acidosis (high and low bicarbonate respectively).
Respiratory acidosis as a primary disorder is often caused by hypoventilation. This can be due to multiple causes including chronic obstructive pulmonary disease, opiate abuse/overdose, severe obesity, and brain injury. When respiratory acidosis occurs, the metabolic response should be to increase the amount of bicarbonate via the renal system. This does not always occur, and renal pathology can easily hinder the appropriate physiological response, leading to increased danger for the patient.
Any pathology that leads to the increased expiration of carbon dioxide can result in respiratory alkalosis. When excess CO2 is expired, the pH of the human body is increased due to less carbonic acid being created. Physiologically, the appropriate compensation is a decreased amount of bicarbonate being created by the renal system. Some causes of respiratory alkalosis include panic attacks with hyperventilation, pulmonary embolism, pneumonia, and salicylate intoxication

Question 33

List cardiac and respiraoty causes of dyspnoea

Answer 33

• Cardiac: AMI, overdose on drugs that slow HR, Eisenmernger, pericardial tamponade, valvular disease, HR or dulated CM, acute/ congestive heart failure, aortic aneurysm, acute decompensated heart failure
• Anemia, cancer, acidosis, sepsis
• Respiratory: PE, (+/- tension) PT, asthma, COPD, hamothorax, Pulmnary infection,

Question 34

List types of pneumonia and briefly describe them

Answer 34

1. Bronchopneumonia
   o Patchy consolidation of the lung.
2. Lobar pneumonia
   o Consolidation of a large portion of a lobe or of an entire lobe.
   Bronchopneumonia
   * Common at the extremes of life.
   * Patchy consolidation of the lung.
   * Extension of a preexisting bronchitis.
   Lobar Pneumonia
   * Acute infection of an entire lobe.
   * Usually due to a virulent organism.
   * Abrupt onset.
   * Now infrequent due to antibiotic treatment.

Question 35

Distinguish between lung volumesand capacities

Answer 35

• Static does not change
• Dynamic can change
• Capacity = two or more volumes

Question 36

List and describe pathogens causing pneumonia

Answer 36

Pathogens: bacterial, fungal, viral; lipid, aspiration

Pneumococcal Pneumonia - “Typical” Pneumonia
- Abrupt onset
- High fever +/- rigors
- Productive cough with usu. purulent sputum
- Shortness of breath
- Pain on breathing (pleuritic)
- Lobar consolidation (or anat segments of lobe) on CXR

Haemophilus influenzae
- Gram-negative coccobacillus ^[may look like a bacillus or a short bacillus which is almost coccus]
- Unencapsulated - less invasive and less virulent
- Capsulated - a, b, c, d, e, f
- H. influenzae B (Hib) most virulent

Haemophilus influenzae Non-Invasive Infection
i.e. not on mucosal surfaces
- Sinusitis
- Otitis media
- Conjunctivitis
- Pneumonia

Invasive Infection (Hib) ^[very rare since vaccination introduced]
- Epiglottis
- Bacteremia
- Meningitis
- Septic arthritis

Neisseria meningitidis

• Gram-negative diplococcus
• Unencapsulated - not often associated with infection - 10-25% of young people carry in pharynx
• Capsulated - A, B, C, W, Y
  
  • Invasive disease
  • Vaccination: Previously only C but now also combined tetravalentA, C, W, Y and standalone B

Neisseria meningitidis Invasive Disease

• Risk factors for invasive disease
  
  • Age <5 years and 15-25 years ^[living in close quarters]
  • Asplenia/hyposplenia
  • Deficiency or **impairment of complement membrane attack complex (C5-C9)
  • Invasive disease:
    
    • Bacteremia (meningococcemia)
    • Meningitis

Moraxella catarrhalis

• Gram-negative diplococcus
• Diseases
  
  • Sinusitis
  • Otitis media
  • Pneumonia
  • Infective exacerbations of chronic obstructive pulmonary disease

Atypical Respiratory Tract Infections

“Atypical” Pneumonia

• “Atypical” bacteria
  
  • Not detectable by Gram stain or cultured by standard methods
  • **Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila, L. longbeachae
• “Atypical” symptoms and signs
  
  • Constitutional symptoms (headache, fever, malaise, nausea) may predominate over respiratory symptoms (dry cough)
  • Less likely to have lobar changes on CXR, diffuse or non-specific infiltrates
• Most cases are milder, but some, especially Legionella pneumophila, C. psittacii, can be severe and life-threatening

Mycoplasma species

• Smallest and simplest bacteria
• Lack of cell wall
  
  • Unable to Gram stain
  • Resistant to cell wall antibiotics e.g. blactam

Mycoplasma pneumoniae

Respiratory

• Pharyngitis
• Otitis media
• Pneumonia

Extrapulmonary

• Meningitis/encephalitis
• Erythema multiforme, tathet lesions
• Autoimmune hemolytic anemia/thrombocytopenia
• Pericarditis/myocarditis

Legionellosis pnumophila and serotypes, longbeachae

• Gram-negative bacillus
• Difficult to see on Gram stain
• Difficult to culture
  
  • Specific growth factors
  • Slow - missed in routine cultures
• Antibody response may take several weeks )(false negative)
• Urinary antigen (Legionella pneumophila) ^[not all subtypes, not longbeachae]
• Nucleic acid amplification ^[not lab validated]

Question 37

Describe complications of bacteria pnumonia

Answer 37

• Complications may be seen in either bronchopneumonia or lobar pneumonia.
• Bronchopneumonia:
  
  • Healing by fibrosis.
• Lobar pneumonia:
  
  • Pleuritis
  • Empyema
  • Abscess formation
  • Haematogenous seeding
  • Death

Organisation / Fibrosis

• Healing by fibrosis rather than resolution is more common in bronchopneumonia.
• Leads to organizing pneumonia.
• Polyps of fibrous granulation tissue within alveoli.
• ‘Masson Bodies’.

Pleuritis

• Inflammation extends to involve the pleura.
• Gives rise to typical pleuritic pain.
• Initially may just be an effusion.
• Followed by fibrinous pleuritis +/- bacteria.
• Healing leads to fibrous adhesions between visceral and parietal pleura.

Abscess Formation

• Localized suppurative process characterized by necrosis of lung tissue.
• Associated with Staphylococcus Aureus and Klebsiella pneumoniae.
• Ranges from millimeters to centimeters.
• Can be single or multiple.
• Macro: Cavities filled with suppurative debris.

Abscess Formation Histology
- Florid inflammation.
- Destruction of alveolar walls.
- Liquefactive necrosis.
- Chronic abscess surrounded by fibrous tissue.

![[Pasted image 20230904191743.png]]

![[Pasted image 20230904191802.png]]

Empyema

• Collection of pus in the pleural cavity is called an empyema.
• Collection usually loculates, followed by scarring.
• Requires drainage.
• Heals by fibrosis.
  ![[Pasted image 20230904191826.png]]
  ## Haematogenous Spread
• Dissemination of bacterial organisms throughout the lungs or other organs.
• Bacteraemia/septicaemia.
• Seeding to heart valves (bacterial endocarditis), meninges (meningitis), kidneys (pyelonephritis).
  ![[Pasted image 20230904191834.png]]

Haematogenous Seeding Examples

• Bacterial endocarditis with vegetations on the aortic valve.
• Brain with surface purulent exudate.
• Kidney with surface petechial haemorrhages.
• Meninges (Meningitis).
• Kidneys (Acute pyelonephritis).
  ![[Pasted image 20230904191845.png]]

Death

• Still one of the commonest causes of death.
• Especially in the very young and old.
• Often represents the terminal event secondary to some other debilitating process.

Question 38

Describe the radiological appearance of pneumonia

Answer 38

Chest radiograph
* airspace opacification
o filling of the alveoli with infectious material and pus
o initially patchy
o becomes confluent as infection develops
* air bronchograms
o air-filled bronchi running through pus-filled alveoli
* complications
o pleural collection
o cavitation
CT chest
* airspace opacification
o looks the same as on a chest x-ray
o degree of consolidation assessed more accurately
* complications can be seen earlier than a chest x-ray
o lung necrosis
o cavitation
o empyema

Question 39

Describe corticosteroids

Answer 39

Inhaled corticosteroids
### Mechanism of action
is complex, and includes although not limited to:
- Reduced airway inflammation and bronchial hyper-reactivity.
- Reduced clonal proliferation of T-helper cells by reducing IL-2 and reduction in cytokines
- Inhibit allergen-induced influx of eosinophils
- Up regulation of beta receptors.

Adverse effects
can be divided into local and systemic effects:
- Local effects (can be minimised by rinsing mouth with water and spit immediately after using. The use of a spacer may also limit local side effects)
- Local infections eg oral candidiasis
- Pneumonia in COPD patients
- dysphonia
- Systemic effects (less common with inhaled compared with systemic, but still occur in some patients particularly at high dose for long periods)
- impaired glucose control
- fractures
- adrenal suppression
- psychosis
- glaucoma
- bruising

Question 40

Describe corticosteroids

Answer 40

Corticosteroids
Mechanism of action:
- enter cells where they combine with steroid receptors in cytoplasm
- enters nucleus where it controls gene transcription:
- synthesis of proteins, including enzymes that regulate vital cell activities over a wide range of metabolic functions including all aspects of inflammation
- formation of a protein that inhibits the enzyme phospholipase A2, which is needed to allow the supply of arachidonic acid (which is essential for the formation of inflammatory mediators)
### Adverse effects
can be divided into local and systemic effects:
- Local effects (can be minimised by rinsing mouth with water and spit immediately after using. The use of a spacer may also limit local side effects)
- Local infections eg oral candidiasis
- Pneumonia in COPD patients
- dysphonia
- Systemic effects (less common with inhaled compared with systemic, but still occur in some patients particularly at high dose for long periods)
- impaired glucose control
- fractures
- adrenal suppression
- psychosis
- glaucoma
- bruising

Question 41

Describe SABAs

Answer 41

SABA – MoA, side effects, indications
Beta agonists relax bronchial smooth muscle by stimulating beta-1 adrenoceptors.
Many of the adverse effects are related to activity on beta-1 adrenoceptors in addition to beta-2 adrenoceptors. Examples include:
- hypokalaemia (note: salbutamol is used to treat hyperkalaemia)
- insomnia
- tremor
- palpitations
- tachycardia
- headaches
- muscle cramps
- lactic acidosis (rarely)
Examples: salbutamol and terbutaline
Onset of action: 5-15 minutes
Duration of action: 3-6 hours
Indications
- first line in managing acute asthema
- symptom relief in asthma and COPD
- prevention of exercise-induced asthma
- previously considered step 1 SABA PRN (as a single agent) only. New guidelines instead recommend LABA (formeterol) with ICS PRN (budesonide) in adult patients
Extra information: high or increasing use indicates poor asthma control

Question 42

Describe adrenaline

Answer 42

Adrenaline is a sympathomimetic agent and an endogenous agonist of the beta receptors.
As a result, it increases total peripheral resistance by increasing vasoconstriction.
Adrenaline relaxes bronchiole smooth muscle. This is used therapeutically to relieve bronchospasm e.g. that occurs during anaphylaxis.
Adrenaline also increases the height of the action potential by lowering the threshold.
It also triggers the secondary messenger cAMP to enact cellular effects downstream.

Question 43

List clincial signs in severe asthma attack

Answer 43

Severe shortness of breath, chest tightness or pain, and coughing or wheezing. Low peak expiratory flow (PEF) readings, if you use a peak flow meter.

Question 44

Describe the respiratory muscles of thorax

Answer 44

• Diaphragm via Phrenic nerve (C3, C4, C5)
• External intercostals (bucket handle movement) via Intercostal nerves
• Accessory muscles: SCM and trapezius via Accessory nerve (CN 11) - recruited e.g. in asthma
• Expiration is passive at rest, but internal intercostals and abdominals are recruited for active expiration
  
  • not always passive at tidal breathing e.g. some postures

Question 45

Describe FV curves in disease

Answer 45

Question 46

Decribe effects of obesity on volumes and capacities

Answer 46

However, intra-abdominal and pleural pressures are increased slightly in obesity, because the downward movement of the diaphragm and the outward movement of the chest wall are restricted when fat accumulates within the thoracic and abdominal cavities [13, 14]. This alters the breathing pattern resulting in a substantial reduction in both the expiratory reserve volume (ERV) and the resting volume of the lung, known as the functional residual capacity (FRC). The reduction in FRC is proportional to the severity of obesity – overweight, mildly obese and severely obese subjects without asthma demonstrate reductions in FRC of up to 10%, 22% and 33%, respectively [15]. Tidal volume is also slightly lower in obese subjects
ERV and TLC also down
Increase in mean respiratory rate and minute ventilation at rest.
Little effect on RV and TLC (small reductions, usually well preserved)
RV: TLC normal or slightly elevated.

Question 47

List structures affected by tension PT

Answer 47

• Pleura
• Lung
• Heart – decreases VR due to increased intrathoracic pressure, decreased SV and CO, BP = haemodynamic compromise

Question 48

Describe Mechanisms of spread S. pneumoniae, H, influenzae, N. meningitidis

Answer 48

The main way people spread Streptococcus pneumoniae to others is through direct contact with respiratory droplets.
- Endogenous pathogen of the URT, can cause otitis media, mastoiditis, sinusitis
- Can disseminate into the LRT or other parts of the body, causing pneumonia, bacteremia, meningitis

S. pneumoniae Capsule - Virulence Factor
enables evasion
- Prevents entrapment in mucus, allowing access to epithelial surfaces
- Protects against phagocytosis and complement-mediated lysis: bacteria persist and multiply
- Anti-S. pneumoniae capsule antibodies (generated through acquired immune response) are protective, but typically not cross-protective
- Vaccine contains purified capsular polysaccharide antigen from many different S. pneumoniae serotypes ^[hence why acquiring one does not necessarily confer immunity against another]
People spread H. influenzae, including Hib, to others through respiratory droplets. People who are infected spread the bacteria by coughing or sneezing, which creates small respiratory droplets that contain the bacteria.

Haemophilus influenzae
- Gram-negative coccobacillus ^[may look like a bacillus or a short bacillus which is almost coccus]
- Unencapsulated - less invasive and less virulent
- Capsulated - a, b, c, d, e, f
- H. influenzae B (Hib) most virulent

General pathophysiology of H. influenzae, M. catarrhalis, and N. meningitidis infection is similar to S. pneumoniae

N. meningitidis: People spread these bacteria by sharing respiratory or throat secretions (saliva or spit)
- Gram-negative diplococcus
- Unencapsulated - not often associated with infection - 10-25% of young people carry in pharynx

• Capsulated - A, B, C, W, Y
  
  • Invasive disease

Question 49

Describe features of atopy

Answer 49

Atopy refers to a predisposition to making IgE antibodies to common environmental proteins such as grass pollens, dust mites, foods, etc. It is:

• Familial, with a number of gene clusters associated
• Can be modified by environmental factors
• Associated with conditions such as eczema, asthma, and food allergies

Question 50

Describe the structure of influenza virus

Answer 50

Influenza Virus Virions
- segmented ssRNA genome
- Haemagglutinin = HA = H
- adheres to cell receptors and enters cell
- RNA synthesis in nucleus
- Neuraminidase = NA = N
- enables release
Note that it is the balance of HA to NA to mediate entry and exit from the cell - in order for infection to be most efficient.

Influenza A viruses split into serotypes based on:
- Haemagglutinin (H) – H1 to H16 known
- Neuraminidase (N) – N1 to N9 known
- H1, H2 & H3 + N1 & N2 in viruses adapted to humans

Symptoms must include a combination of the following:
- central: headache
- systemic: fever
- muscular: tiredness (due to IFN effect)
- joint aches
- coughing
- GI upset
- nasopharyngeal symptoms

Ecology of Influenza Viruses
- Endemic in multiple species
- Birds (domestic and wild)
- Pigs
- People
- Can move between these if species barriers can be overcome

Influenza Virus Nomenclature
- Divided into A, B, and C
- A is the most prevalent cause of human infection
- B also circulates

Influenza A viruses split into serotypes based on:
- Haemagglutinin (H) – H1 to H16 known
- Neuraminidase (N) – N1 to N9 known
- H1, H2 & H3 + N1 & N2 in viruses adapted to humans

Isolates Named After Place of Isolation, Year & Type:
- A/Brisbane/59/2007 (H1N1)
- A/Uruguay/716/2007 (H3N2)
- B/Florida/4/2006

Note that place of isolation does not mean place of origin.

Immunity to Influenza
Innate immunity, especially interferons, are strong.
T cells are required to clear an infection.
Antibodies that recognize HA and NA are most important for preventing re-infection with exactly the same strain.
- Anti-HA is a classic neutralizing antibody: blocks the binding of HA to its receptor.
- Anti-NA is protective but not neutralizing (because it mediates exit but not entry).

Genetic and Antigenic Drift - Evolution in Action
- A low fidelity polymerase + high replication rate result in a relatively rapid mutation rate.
- A high percentage of infectable individuals have protective antibodies to HA and NA, creating strong selective pressure to change these proteins, evade antibody recognition, and reinfect.

Genetic and Antigenic Shift - Flu as a Genetic Engineer
- If two strains co-infect a single cell, segmented genomes can ‘re-assort,’ creating new strains ^[just a byproduct of assembly, cell cannot distinguish between strain A and B].
- Co-evolution of a strain and its host creates a species barrier, and genetic shift can break or lower species barriers.
- note that statistically only a small amount is pathogenic
- with multiple rounds of replication becomes more feasible

Question 51

Describe COVID

Answer 51

• Corona – ‘Crown’
  
  • (+)ssRNA virus
  • Large RNA genome ~29kB
  • 14 ORFs (both large and small)
  • Ribosomal frameshifting
  • 29 gene products
• Host-derived envelope ^[i.e. stolen]
• Spherical
• 100-160nm
• Protruding spike proteins ^[critical, binds to ACE2 receptor, target of vaccination]

SARS-CoV-1 v SARS-CoV-2
- SARS-CoV-1
- 8110 cases, 811 deaths: CFR ~10%
- SARS-CoV-2
- 608m (confirmed) cases, 6.5m deaths: CFR ~1% (falling)

Note that the CFR for SARS-CoV-2 is much lower than SARS-CoV-1.

• SARS-CoV-2
• Higher tropism for the URT
  - With evolution increases affinity
  - More efficient host-cell invasion
  - Increased spread
• **Higher virus loads prior to symptoms
  
  • Pre-symptomatic/asymptomatic spread - it is this factor that contributed to the much greater spread of SARS-CoV-2
  • Note also that CoV1 cases are much easier to identify and isolate given that symptomatic individuals had higher load ^[this idea contributed to complacency in COVID-19]
• BOTH
  
  • Attach via ACE-2
  • Respiratory pathogens
  • Stronger binding to ACE-2 = virus is now adapting to avoid ACE-2, or bind less well, in favour of another receptor

The notable feature in this diagram is the viral genome which peaks in the pre-symptomatic phase (within the URT).
Consider also that a proportion of the population will be complete asymptomatics.
Note also that those with severe illness are theorised to have poorer innate immune systems (IFN). Viral genome curve shifts to the left.

Respiratory Tract and Beyond….
- SARS-CoV-2 does not stay in the respiratory tract
- Found viral RNA at autopsy:
- Digestive tract tissue – (-ve RNA)
- Brain tissue + CSF
- Heart tissue– 2/3rds of patients who died of pneumonia!
- Multisystem disease (severe illness) ALSO includes:
- Renal insufficiency
- Reduced liver function
- Blood clotting ^[treat to drastically improve outcomes]

• Arrhythmias, hypertension, and cardiac dysfunction in long COVID
• Direct invasion of cardiomyocytes
  
  • Damages/destroys the cells
  • Dampens ACE-2 function: Usually plays a role in regulating blood pressure.
• Cardiac tissue immunopathology
  
  • Myocardial injury – 5 of the first 41 patients in Wuhan

COVID-19 Highlights Diverse Outcomes
- SARS-CoV-2 can cause:
- Asymptomatic
- Never develop COVID-19 symptoms
- + RNA test
- Mild
- Symptoms self-limiting
- Severe
- Life-threatening
- Requires critical care
- Long-COVID ^[note also that long COVID fairly common, poorly understood and not well acknowledged]
- Symptoms beyond 4 weeks
- RNA test

Question 52

Describe rhinovirus

Answer 52

Rhinovirus – A Picornavirus
- Picornavirus (literally ‘very little RNA virus’).
- A large family of very small +ve sense RNA viruses.
- Collectively they are a nasty bunch, with rhinoviruses accounting for more specimens tested than influenza.
- Other members include Polio, Coxsackievirus (causes myocarditis), and Foot and Mouth Disease Virus (of livestock).
- note rhinoviruses are more of an economic problem than a cause of serious disease, but account for more specimens tested than influenza
Rhinovirus (Picornavirus) Genome
- Genome is translated immediately upon entry.
- Viral RNA pol is not carried in the virion.
- A single open reading frame generates a polyprotein, processed by a viral enzyme.
- Note: 5’-UTR has many AUGs therefore ribosome cannot start at the beginning and scan for first AUG
- therefore has to jump onto RNA at rifht place– has IRES which allows ribosome to bind at internal position, which differes mechanistically from host translation
- this enables virus to stop host translation but preserve its own
- IRES has biorech appliactions

Rhinovirus – A Family Affair
- Most frequently isolated agent from people with the ‘common cold.’
- Children have more frequent infections than adults.
- “The family unit is a major site for the spread of rhinoviruses in contemporary society.”
- “Infections are generally brought into the home by children.”
- Secondary attack rates are 30-70%, with spread most common for other children and mothers.
- Secondary infections appear at 2-5 day intervals, most within a few days of the index case.
- The greater the symptoms of the index, the higher the attack rate.

Note that rhinoviruses are not enveloped and thus harder to disinfect.

Question 53

Describe adenovirus

Answer 53

Adenoviruses
- Adenoviruses (AdV) were found in the 1950s using cell culture and were associated with human respiratory disease.
- Human AdV has 6 species (A-F) and 51 serotypes.
- Characteristics include a linear, dsDNA genome ~35 kb, non-enveloped virion, and replication in the nucleus.

Adenoviruses Do Lots of Nasty Things
- Diseases caused by Adenoviruses include upper respiratory infections, gastroenteritis, meningoencephalitis, hepatitis (in kids with transplants), myocarditis, acute hemorrhagic cystitis, and more.
- Different serotypes cause different disease

Adenovirus – An Example of Tropism
- Tropism = predilection for certain cell types or tissues.
- Adenovirus fiber directs cellular tropism.
- Swapping fibers between serotypes redirects tropism. ^[but does not explain the full picture]
- Most serotypes seem to get to the GI tract, but why only a few cause disease is not known.
- Tropism can be altered in immunocompromised individuals.

Diagnosis – All Viruses
Samples to Detect Virus:
- Throat swabs.
- Nasopharyngeal aspirates (NPA) or washes.
Tests to Detect Virus:
- PCR, often a combined test for multiple pathogens.
- Immunochromatographic (ICT) tests (dip sticks).
- ELISA.
- Immunofluoresecence on cells from samples
Tests for Past Exposure:
Test serum for antibodies (ICT, ELISA).
- Remember, it takes time, especially IgG, and is complicated by maternal antibodies in very young individuals.

Question 54

Describe RSV

Answer 54

RSV – From the Family: Paramyxoviridae
- A big family with two branches: Paramyxovirinae and Pneumovirinae.
- RSV belongs to the Pneumovirinae branch, along with Human Metapneumovirus.

RSV shares similarities in types of surface proteins with orthomyxoviruses e.g. influenza

Respiratory Syncytial Virus (RSV)
- Enveloped capsid with helical symmetry.
- Negative (-ve) sense RNA genome.
- note two forms when cultured: spherical or filamentous (which could constitute infectious form)
- Makes 10 mRNAs, one for each gene, and replication is entirely in the cytoplasm.
- no splicing or polyproteins

How Much of a Problem Is RSV?
- Highly seasonal in temperate climates, with RSV ‘season’ coinciding with winter – early spring.
- On first exposure, 25% to 40% have bronchiolitis or pneumonia, and 0.5% to 2% will require hospitalization.
- Hospitalizations with RSV mostly involve infants less than 6 months old.

Who Gets Sick with RSV and When?
- Highly seasonal in temperate climates, with RSV ‘season’ coinciding with winter – early spring.
- On first exposure, 25% to 40% have bronchiolitis or pneumonia, and 0.5% to 2% will require hospitalization

Hospitalisations:
- Most (~60%) are infants < 6 months old
- Nearly all (>90%) are < 1 year old
- Anything that compromises breathing, cardiac, or immune function predisposes to the risk of severe RSV (premature babies at risk)
- These risk factors exist in adults as well.

RSV Pathogenesis
- Virus-induced
- Immunocompromised individuals are at risk.
- But direct virus damage is limited.
- Disease is largely caused by immunopathology. ^[an over-reaction as opposed to histological changes]
- The narrowing of bronchioles is due to inflammation and not direct virus damage.
- Appropriate immune response is a tricky balance.

Transmission
- Transmitted by droplets, large particles, and fomites.
- Incubation time is 4-6 days.
- Infectious for 3-8 days after symptoms.
- Not especially stable but can survive a few hours on nonporous surfaces.
- Medical personnel transmit these viruses readily.
- Also childcare.
- Toys can be good vectors too.
- Nosocomial infection is an enormous problem, especially as many infants at high risk of severe infection are already in the hospital.

Treatment and Prophylaxis
Treatment
- Supportive care.
- Use of antivirals (ribavirin) not well supported by evidence.
Prophylaxis
- No vaccine.
- Early trial of formalin-inactivated vaccine a disaster.
- Immunized kids had more severe infections.
- Potentially the wrong ‘type’ of immunity generated.
- Palivizumab (Synagis) given monthly to babies at high risk. ^[e.g.?]
- Studies mixed as to the reduction of disease.
- Costs approximately $1000 a shot and is not on the PBS.

Question 55

Describe common causes of CAP

Answer 55

In hospitalised patients, commensal flora changes:
- E. coli and other Gram negatives
- Pseudomonas aeruginosa
- Staphylococcus aureus
- All of the above may colonize the URT and then cause LRTI

“Typical” Pneumonia
Pneumonia:
- Abrupt onset
- High fever +/- rigors
- Productive cough with usu. purulent sputum
- Shortness of breath
- Pain on breathing (pleuritic)
- Lobar consolidation (or anat segments of lobe) on CXR

S. pneumoniae Capsule - Virulence Factor
enables evasion
- Prevents entrapment in mucus, allowing access to epithelial surfaces
- Protects against phagocytosis and complement-mediated lysis: bacteria persist and multiply
- Anti-S. pneumoniae capsule antibodies (generated through acquired immune response) are protective, but typically not cross-protective
- Vaccine contains purified capsular polysaccharide antigen from many different S. pneumoniae serotypes ^[hence why acquiring one does not necessarily confer immunity against another]

Haemophilus influenzae
- Gram-negative coccobacillus ^[may look like a bacillus or a short bacillus which is almost coccus]
- Unencapsulated - less invasive and less virulent
- Capsulated - a, b, c, d, e, f
- H. influenzae B (Hib) most virulent

Haemophilus influenzae Non-Invasive Infection
i.e. not on mucosal surfaces
- Sinusitis
- Otitis media
- Conjunctivitis
- Pneumonia

Invasive Infection (Hib) ^[very rare since vaccination introduced]
- Epiglottis
- Bacteremia
- Meningitis
- Septic arthritis

Neisseria meningitidis

• Gram-negative diplococcus
• Unencapsulated - not often associated with infection - 10-25% of young people carry in pharynx
• Capsulated - A, B, C, W, Y
  
  • Invasive disease
  • Vaccination: Previously only C but now also combined tetravalentA, C, W, Y and standalone B

Neisseria meningitidis Invasive Disease

• Risk factors for invasive disease
  
  • Age <5 years and 15-25 years ^[living in close quarters]
  • Asplenia/hyposplenia
  • Deficiency or **impairment of complement membrane attack complex (C5-C9)
  • Invasive disease:
    
    • Bacteremia (meningococcemia)
    • Meningitis

Moraxella catarrhalis

• Gram-negative diplococcus
• Diseases
  
  • Sinusitis
  • Otitis media
  • Pneumonia
  • Infective exacerbations of chronic obstructive pulmonary disease

Question 56

Describe causes of atypical pneumonia

Answer 56

• “Atypical” bacteria
  
  • Not detectable by Gram stain or cultured by standard methods
  • **Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila, L. longbeachae
• “Atypical” symptoms and signs
  
  • Constitutional symptoms (headache, fever, malaise, nausea) may predominate over respiratory symptoms (dry cough)
  • Less likely to have lobar changes on CXR, diffuse or non-specific infiltrates
• Most cases are milder, but some, especially Legionella pneumophila, C. psittacii, can be severe and life-threatening

Question 57

Describe advantages and disadvantages of inactivated vaccine

Answer 57

Killed or inactivated vaccines contain an inactive preparation of a pathogen.
It is less effective than live vaccines i.e. less immunogenic. However, it is more effective if antigen is a protein, and if adjuvant used.

Inactivated vaccines require booster doses to maintain efficacy.
It predominantly generates humoral immunity based on production of neutralising antibodies, with rapid production on re-exposure.

There is a limited cellular immune response due to absence of replicating organisms, and reduced production of secretory IgA.

Examples of inactivated vaccines include polio (Salk), influenza, HepA, rabies, pertussis, cholera.

Advantages
- safety
- easy to produce and store
- less affected by pre-existing antibody (maternal antibody can interfere with the response to immunisation)
#### Disadvantages
- requires boosters
- may not preserve the immunoprotective antigen
- poor induction of T cell immunity (CD8+)
- poor inducers of mucosal immunity
- potential for immune response to tissue antigens derived *from cells to which vaccine is produced (allergy)**

Question 58

Describe mechanisms of antibiotic resistance

Answer 58

Mycoplasma species= NO CAPSULE, RESSITANT TO CELL WALL antibiotics e.g. beta lactams
Capsules Confer Resistance to Phagocytosis**

• Capsules hide the bacterial targets (PAMPs) of the phagocytic receptors (PRRs).
• The phagocytic response of the innate immune system is (temporarily) inhibited.
  
  • APCs cells unable to present antigen to T-cells (via MHCII molecules).
  • Bacteria continue to replicate.
• BUT… Immune system has evolved to develop a T-cell/thymus independent (TI) response to deal with encapsulated bacteria that avoid stimulating T-cell responses.

Question 59

cALCULATE PAO2

PaO2 if PaCO2 is 3 and at 55 kPa, RQ 0.8

Answer 59

PaO2 if PaCO2 is 3 and at 55 kPa, RQ 0.8
Ideal alveolar gas equation
Concentration that would exist if V = Q.
PAO2 = FiO2 x (PB - SVP H2O) – (PaCO2/RQ)
= 0.21*713 – (55/0.8) = 82

Question 60

Describe the pleura

Answer 60

The pleura is a serous membrane that envelopes each lung. The membrane is made up of a visceral layer that is adherent to the lung, and a parietal layer that is fixed to the inner thoracic wall, lower cervical vertebra, costovertebral area, mediastinum, and diaphragm. There is a potential space between the parietal and visceral layers known as the pleural cavity. The cavity is filled with serous fluid that allows the parietal and visceral layers to freely glide over each other during breathing; thus, reducing the impedance to the breathing mechanism.
At their most basic level, each long is characterized by its apex and base; the apex projects towards the superior thoracic aperture, while the base is placed on the diaphragm. Alternatively, we can describe the lung as having four pleural surfaces (costal, cervical, medial and diaphragmatic) . The two pleura are separate and non-continuous, although they do “break” to form the hila.

Question 61

Describe asbestos and associated disease

Answer 61

Asbestos
Asbestos exposure has been associated with a number of
pathologic changes in the lungs and pleura, as listed
below:
1. Interstitial fibrosis
2. Benign serous pleural effusion
3. Bronchogenic carcinoma
4. Malignant mesothelioma
5. **Fibrous plaques of the parietal pleura

Several types of bodies: crocidolite, chrysotile, amosite, anthrophyllite
Asbestosis part of umbrella: pneumoconiosis
are a lung reaction to inhalation of mineral dust, organic dust, chemical fumes and vapors.

Examples include:
- carbon and coal workers pneumocnoisos
- silica or silicosis
- asbestos or asbestosis
- insecticides
Factors affecting development of lung disease
– Duration and length of exposure
– Amount of retained dust
– Size (small1-5 microns- can reach and settle in small
alveoli)
– Shape, buoyancy of the particles
– Particle solubility (insoluble particles can remain in
the lungs for years)
– Additional irritants (SMOKING!!!!)
– Preexisting lung disease

Asbestos
* Pleural plaques: fibrosis in parietal and visceral pleura
* Diffuse pulmonary fibrosis (Asbestosis)
* Recurrent Pleural effusions
* Lung carcinoma
* Mesothelioma (lung and abdominal) - incidence high
* Other cancers (trachea, larynx, gastrointestinal
tract, others?)

Identified by asbestos bodies. usually colourless, but if iron deposits, can see (ferrogenous bodies). No need to see in order to diagnose

Question 62

Describe how to treat pneumonia

Answer 62

Pneumonia can be bacterial or viral.
If viral, treat with
- Rest
- Oxygenation
- Fluids
Bacterial: CAP or HCAP (HAP or VAP)
If bacterial and community acquired, treat with IV doxycycline/oral macrolides (clarithromycin) prescribed empirically – if no comorbidities.
Depends on pathogen and resistance.
Physiotherapy may be required.

Question 63

Describe anatomy of lungs

Answer 63

Lung relational anatomy: The lungs lie either side of the mediastinum, within the thoracic cavity. Each lung is surrounded by a pleural cavity, which is formed by the visceral and parietal pleura. Each lung occupies the respective hemithorax.

the left and right lung differ slightly in their morphology.
The left lung is slightly smaller in size due to the presence of the cardiac notch, where the apex of the heart sits, and has only two lobes, and one fissure.
The hilum is bordered by the free edge of the visceral pleura and contains:
- pulmonary artery
- left main bronchus
- closely followed by bronchial vessels
- pulmonary veins
- broncho-pulmonary lymph nodes

![[Pasted image 20230821093648.png]]

^[question: compare and contrast the hila, lungs]
The right lung by contrast is larger, and contains three lobes and two fissures.
The right lung hilum contains:
- pulomary arteries
- bronchial vessels
- pulmonary veins
- superior lobar bronchus
- ingerior and middle lobar bronchus
- all three are contained within the right main bronchus
- bronchi-pulmonary lymph nodes

Note that the 1st division of the primary bronchus occurs in the hilum. Thus pulmonary arteries and veins also follow this division.

Bronchopulmonary segments
![[Pasted image 20230821093718.png]]
Both left and right lung have the same number of segments, despite differing numbers of lobes.
There are 10 segments for each lung, and they constitute distinct anatomical, functional and surgical units.
As they stand alone, if a tumour grows within a single segment, it can be resected and the lung can continue to function.

Within the left lung there is an even split of the segments between the superior and inferior lobes.

![[Pasted image 20230821093726.png]]

Bronchial tree
![[Pasted image 20230821093740.png]]
Note: there are three lobar bronchi as there are three lobes in the right lung.

![[Pasted image 20230821093748.png]]

![[Pasted image 20230821093757.png]]
Note that the bronchial tree can be divided into conduction and respiratory portions.
- the conduction portion is made up of the bronchi, bronchioles (terminal)
- the conduction portion is responsible for filtering (?), warming and humidifying air
- bronchi (segmental and subsegmental) have cartilage and smooth muscles, and continue for 10 generations
- bronchioles have smooth muscles, and go for 11-16 generations
- the respiratory portion is made up of respiratory bronchioles and alveoli, and these go for 17-23 generations

Note: terminal bronchioles lined with smooth muscle, but it is more distinct and classed separately from bronchiolesz
the left and right lung differ slightly in their morphology.
The left lung is slightly smaller in size due to the presence of the cardiac notch, where the apex of the heart sits, and has only two lobes, and one fissure.
The hilum is bordered by the free edge of the visceral pleura and contains:
- pulmonary artery
- left main bronchus
- closely followed by bronchial vessels
- pulmonary veins
- broncho-pulmonary lymph nodes

^[question: compare and contrast the hila, lungs]
The right lung by contrast is larger, and contains three lobes and two fissures.
The right lung hilum contains:
- pulmonary arteries
- bronchial vessels
- pulmonary veins
- superior lobar bronchus
- inferior and middle lobar bronchus
- all three are contained within the right main bronchus
- bronchi-pulmonary lymph nodes

Note that the 1st division of the primary bronchus occurs in the hilum. Thus pulmonary arteries and veins also follow this division.

Bronchopulmonary segments
Both left and right lung have the same number of segments, despite differing numbers of lobes.
There are 10 segments for each lung, and they constitute distinct anatomical, functional and surgical units.
As they stand alone, if a tumour grows within a single segment, it can be resected and the lung can continue to function.

Within the left lung there is an even split of the segments between the superior and inferior lobes.

Bronchial tree
Note: there are three lobar bronchi as there are three lobes in the right lung.
Note that the bronchial tree can be divided into conduction and respiratory portions.
- the conduction portion is made up of the bronchi, bronchioles (terminal)
- the conduction portion is responsible for filtering (?), warming and humidifying air
- bronchi (segmental and subsegmental) have cartilage and smooth muscles, and continue for 10 generations
- bronchioles have smooth muscles, and go for 11-16 generations
- the respiratory portion is made up of respiratory bronchioles and alveoli, and these go for 17-23 generations

Note: terminal bronchioles lined with smooth muscle, but it is more distinct and classed separately from bronchioles

Question 64

Describe how oxygen diffusion changes with disease

Answer 64

• Perfusion vs Diffusion for Oxygen
  
  • Normally perfusion limited (0.2-0.3s equilibration with capillary blood)
  • Gas exchange impaired if diffusion membrane affected, to the point where oxygen becomes diffusion limited instead of perfusion limited:
    
    • initially this will only be seen with decreased capillary transit times (e.g. exercise)
    • (can happen at rest with severe conditions)
• Clinical Implication: Impaired diffusion membrane affects gas exchange, especially for oxygen

Question 65

Describe the neurons invovled in respiratory control

Answer 65

• Respiratory Centre
  
  • Located in the medulla
  • Drives ventilation rate and volume via afferents to respiratory muscles’ motor nerves ^[causes contraction]
• Neuronal Groups
  
  • Dorsal Respiratory Group
    
    • Primarily inspiratory neurons - sending out signals
  • Ventral Respiratory Group
    
    • Caudal: Mix of inspiratory and expiratory neurons
    • Rostral: Airway dilator functions
    • Pre-Botzinger Complex: Likely central pattern generator site ^[pattern of breathing, start and stop]
  • Botzinger Complex
    
    • Expiratory neurons
  • Pontine Respiratory Group
    
    • Fine control of respiration, influences medullary respiratory center
• Cortex
  
  • Voluntary breathing interruption, e.g., singing, talking ^[aka influence pattern of breathing]

Respiratory Cycle and Neuronal Firing
- No single pacemaker is responsible for generating respiratory activity ^[c.v. cardiac]
- Likely a complex interaction of different groups of neurons (6 - half and half):
- Early inspiratory, inspiratory augmenting, late inspiratory
- Expiratory decrementing, expiratory augmenting, late expiratory
- Firing of neurons results in three respiratory phases:
- Inspiratory ^[turn on signals, get muscles involved]
- Expiratory Phase 1 (passive) ^[i.e. recoil of lungs]
- Expiratory Phase 2 (active) ^[turning on signals, get muscles involved]
- Influences on Respiratory Phases
- Various inputs, with CO2 being the most important
- CO2 influences central chemoreceptors

Question 66

Describe the role of surface tension and surfactant

Answer 66

• Surface Tension (ST)
  
  • Force across liquid surface (across imaginary line 1 cm long)
  • Develops at air-water interfaces
  • Greater forces between water molecules than water and gas molecules: liquid surface area becomes as small as possible
  • Result: alveolus has tendency to collapse on itself ^[like a bubble]
• Law of Laplace
  
  • Pressure = 2 x ST/radius
    
    • radius inversely proportional to pressure
    • alveoli would collapse if it weren’t for surfactant, reducing surface tension as radius decreases
• Surfactant
  
  • Lipid (90%) fluid from type II alveolar cells
  • Majority phospholipid: mainly dipalmitoyl phosphatidyl choline (DPPC): hydrophilic end faces alveolar fluid lining alveoli, hydrophobic end faces gas filled alveolus
  • Acts as detergent, reducing water molecule attraction, thus **reducing surface tension and preventing collapse
  • Decreases ST as lung volume decreases: as lung vol decreases DPPC squeezed together, decreases water-water interaction and thus decreases surface tension
    Note: relevant in compliance

Question 67

Describe the clinical implications of respiratory mechanics

Answer 67

• Flow in Large Airways
  
  • Predominantly turbulent flow
  • frictional forces influences flow (come from lining of airway wall– increases with scarring)
  • note: driving pressures really high, so overall frictional forces do not influence flow
• Gas Density
  
  • Different gas densities (e.g., Heliox - gas mixture) to improve flow and oxygen delivery to alveoli
  • more laminar flow due to He low density– get into alveoli more easily
• Flow in Small Airways
  
  • Predominantly laminar flow, resistance most important factor
    
    • Viscosity and length are essentially fixed
    • radius of airway is the most important factor determining resistance
• Factors Affecting Airway Radius
  
  • Internal: Fluid, smooth muscle hypertrophy/contraction
  • External: Lung volume, external compression of airway ^[e.g. haemothorax]
• Compliance
  
  • Extent of lung expansion per unit increase in transpulmonary pressure
  • Factors influencing decreased compliance
    
    • Physiological: Age, posture (lying flat is worse), decreased lung volumes
    • Pathological: Fibrosis, alveolar overdistension (COPD over PEEP), chest wall deformities, obesity
• Time Constants (τ)
  
  • if initial rate of change continued, at what time would process have been completed
  • alveolar filling and emptying is an exponential process, measured by t
    
    • one t = 63%
    • 3t = 95%
  • τ = resistance x compliance
  • normally in 0.2s, alveolar filling emptying 95% complete at 0.6s
• Fast and Slow Alveoli (imp)
  
  • resistance and compliance not uniform across lung, therefore t varies
  • Fast: Low resistance, compliance, or both (e.g., pulmonary fibrosis): empty and fill quickly
  • Slow: High resistance, compliance, or both (e.g., COPD): empty and fill slowly

Question 68

Desribe passive and active factors that determine pulmonary vascular resistance

Answer 68

• Passive Factors
  
  • Pulmonary Blood Flow: Adapts to large changes in cardiac output with small increases in pulmonary arterial pressure; PVR decreases as flow increases
    
    • Distension: Thin-walled vessels distend easily with increased flow
    • Recruitment: Increased flow opens previously closed pulmonary vessels
  • Lung Volume:
    
    • Optimal PVR at FRC
    • low lung vols = compression of extra-alveolar vessels
    • high lung vols = compression of alveolar vessels
  • Gravity: Lung and pulmonary vessels act as starling resistor: flow through tube is influenced by driving pressure (coming through) and pressure around tube
    - divides lung into 3 zones (West’s zones)
    - 1:alveolar pressure>arterial>venous -
    - no flow
    - effectively dead space
    - not really seen in absence of pathology ^[or can make one]
    - 2:arterial>alveolar>venous
    - flow dependent on alveolar volume
    - 3:arterial>venous>alveolar
    - flow occurs independently of alveolar volume, an effective shunt
• Active Factors
  
  • Hypoxic Pulmonary Vasoconstriction:
    
    • most important factor
    • key difference between systemic and pulmonary vasculature
    • protective: to optimise VQ matching across lung - away from ‘hypoxic’ areas e.g. pus filled infected areas
    • **Primarily mediated by alveolar PO2, arterial plays small role ^[like metabolic regulation of systemic vessels]
    • Mechanism: ^[debated]
      
      • Hypoxia inhibits K+ channels, opens VGCa channels (L-type), leads to Ca influx, smooth muscle contraction
      • Biphasic response: Rapid decrease then slower increase; PBF halves in first 5 min then plateaus, second slower increase around 40 min
    • Modulated by various factors: Inhibition (alkalosis, nitric oxide - dilator, prostacyclins, volatile anaesthetics) and enhancement (acidosis, hypercapnoea, hypothermia, endothelin): increases vascular tone
  • Neural Control:
  • Sympathetic (mixed effects): alpha 1 and vasoconstriction (NA response), beta 2 and vasodilation (Ad response)
  • para-sympathetic (vasodilation, via M3 receptor)
  • Humoral Control: Vasoconstriction (noradrenaline, adrenaline, thromboxane, serotonin, histamine) and vasodilation (prostacyclins)

Question 69

Describe the role of Hb as a buffer

Answer 69

Hemoglobin as a Buffer

• Hemoglobin (Hb) can bind and release H+, acting as a buffer.
• CO2 produced by tissues is quickly converted into HCO3- and H+.
• Hb.O2 and Hb.H participate in reactions in tissues and lungs.
  
  • H binds Hb and displaces oxygen in tissues; H increases as cells are metabolically active – conditions optimised for release
  • the reverse occurs in lungs (in order to deliver oxygen from lungs in tissues)
• The Bohr effect describes how pH affects the Hb dissociation curve.
• This process is streamlined: Hb affinity for oxygen decreases, so can bind H as pH decreases

Question 70

Describe Bohr effect

Answer 70

Note the reaction is bi-directional/reversible
- depends on context
- acidity decreases affinity for oxygen (right shift)
- alkalinity increases it (left shift)

Recall from [[Physiology Lecture 10]] that temperature and CO2 also affect affinity of Hb for oxygen.

Question 71

Descrieb respiartory disorders

Answer 71

Respiratory Disorders
- Obstructive Sleep Apnea:
- e.g. to age, enlarged tonsils, obesity
- loss of muscle control of soft palate, tongue, pharyngeal dilator muscles
- falls into oropharynx to occlude breathing
- chemoreceptors shift at point in order to tolerate high pCO2 resulting in a loss of both voluntary and involuntary control, apnoea
n.b. respiratory paradox: chest is sucked in, abdomen out

• Central Sleep Apnea: completely different, related to diaphragm ^[innervate to treat]
• Sudden Infant Death Syndrome (SIDS): Disorder of homeostasis where infants with brainstem abnormalities struggle with metabolic challenges during sleep.
  
  • cant adjust to or defend against asphyxia or other challenges

Other Conditions

• Ondine’s Curse: cannot breathe involuntarily but CAN voluntarily. Must be ventilated
• Cheyne-Stokes Respiration: cycles of erratic breathing and apnoea. Opioids can create this
• Kussmaul Breathing: i.e. in DKA, ketones results in acidosis. Patient compensates with hyperventilation. Rapid AND deep breathing. Minute ventilation is very high, and bicarbs low ^[mixed disorder]

Question 72

Describe the effects of exercise and altitude on breathing

Answer 72

Exercise

• CO2 does not change significantly, except at peak activity with a bit of hyperventilation, despite augmented metabolic conditions, and changes to respiratory rate
• O2 is also maintained
• Thought to be a mix:
  
  • cortical control
  • SNS activation
  • muscle stretch and mechanoreceptors
    All of these increase minute ventilation

Note: what does change is oxygen uptake, and venous oxygen content as a result.

Note 2: in heart disease, no VQ match- results in deadspace.

Altitude
- Everest: 8848m
- Atmospheric pressure: 33% of sea level (pO2 54 vs. 160 mmHg)
- Alveolar pCO2: 7 vs. 35
- Alveolar pO2: 35 vs. 100 - low even with compensation
- Acclimatization:
- Hb 15 g/dl
- EPO increased
- Hyperventilation and decreased CO2
- Acute alkalosis (pH 7.7)
- 2,3 DPG increased
- Peripheral chemoreceptors active
- Central chemoreceptors CO2 sensitivity increased
- O2-Hb Dissociation Curve shifts

• But, takes days to weeks

Side note on COPD:
- severe, always hypoxic - set point changed: supplementing with 100% o2 reduces drive and results in paradoxic hypoxia: so saturate with normal O2 (for patient)
- chemoreceptors are desensitised i.e. pick up at higher pCO2
- peripheral receptors are key drivers

Question 73

Describe nasal cavity

Answer 73

Nasal cavity
- Houses receptors for olfaction
- adjust temperature and humidity of inspired air
- trap and remove particulate matte from airway by filtering air through hair in vestibule; trapping foreign material in abundant mucus (i.e. first line of defence, physical barriers, see [[Immunology Lecture 2]])
^Gray’s

note the choanae or entry into the pharynx
note also the minor and major alar cartilages as part of the nasal lateral wall
note too the uncinate processes, which separate components of spaced between conchae and direct air flow

Skeletal framework of nasal cavity
The skeletal framework of the nasal cavity is comprised of the following bones:
- nasal
- maxilla
- ethmoid (which extends into cranial cavity, crista galli, cribriform plate where olfactory bulb sits. note dura mater attaches here)
- vomer
- lacrimal
- inferior concha
- palatine
- sphenoid (medial pterygoid)

The septum is composed of septal cartilage, vomer, and perpendicular plate of the ethmoid bone.

The nasal cavity can be categorised into three regions:
- the nasal vestibules - small space, just internal to naris (Anterior opening). It is lined by skin and contains hair follicles ^[Gray’s for students]
- respiratory regions - largest part. Well vascularises and supplied by nerves. Lined by respiratory epithelium (mainly ciliated and mucous cells) [see [[Histology Lecture 2]]]
- olfactory regions - small, at apex. Lined by olfactory epithelium, contains olfactory receptors.

Question 74

Describe paranasal sinuses

Answer 74

There are four groups of paranasal sinuses:
- frontal (bilateral) and mostly superiorly
- sphenoidal (midline) - more posteriorly
- ethmoidal (‘air cells’) - superior aspect
- maxillary - laterally
![[Pasted image 20230816214744.png]]
Not included in this table is the semilunar hiatus

Notable features include:
- ethmoidal bulla under middle conchiae
- uncinate process which controls air flow

Note: drainage of sinuses usually follows gravity i.e. draining downwards, with the exception of the sphenoidal sinus, which drains into an adjacent structure (the spheno-ethmoidal recess, above the superior nasal concha)

Note 2: naso-lacrimal duct drainage explains why sniffly nose when crying

Functions of paranasal sinuses
- reduction of skull weight (Debated)
- resonance of voice
- protection
- humidification – due to mucosal lining

Question 75

Descrieb complements

Answer 75

Complement
- Soluble proteins produced mainly by the liver
- “Complements” antibodies, enhancing opsonization and bacterial killing
- Sequential cascade activation upon pathogen presence, culminating in pathogen killing
- Cascade amplifies response

Complement Proteins
- Names can be confusing
- Some named C followed by discovery number (e.g., C4, C5)
- Others without C are part of alternative or lectin pathways

Complement Activation
- Most proteins activated by proteolysis
- Many proteins are proteases
- Activated proteins cleave and activate next proteins in cascade
^[note: does larger fraction typically activate?]

Classical Complement Pathway
- most recent evolutionarily, despite name
- C1, C4, C2, C3, C5, C6, and C7 (though not in that order)
- “Membrane attack complex” formed from C6, C7, C8, and C9: forms pore in membrane, disrupts ion balance, and results in pathogen cell death
- In total, 3 pathways activate C3: 3 pathways of complement activation

Notes on the pathways
- all pathways culminate in cleavage of C3, resulting in formation of MAC, binding to C3b receptors to engulf and destroy pathogen, and recruitment of inflammatory mediators to site of infection
- all pathways occur on the cellular membrane ^[which?]

Functions of Complement
- Membrane attack complex
- Active intermediaries (C3a, C4a, C5a) - anaphylatoxins, inflammatory cell recruitment (chemoattract properties) ^[?]
- Opsonization - Complement deposition aids phagocytosis
- Complement receptors augment B cell activation (especially if no T help)
- Complement receptors assist B cells in transporting non-cognate antigens to lymph nodes, where the reactive B or T cell can interact with it

Question 76

Describe regulation of complement and how to interpret results

Answer 76

Regulation of Complement
- Regulatory proteins: C1 inhibitor, Factor H, Factor I, CD59
- c1 inhibitor targets begining of cascade, and keeps C1 contolled
- H and I targets middle of cascade, targets products of cascade, binds and prevent activation – controlling C3 deposits
- CD59 at end of cascade, inhibits final assembly

Evaluating Complement in Diagnosis
- Serum testing for complement component levels
- C3 and C4 levels tested in practice
- intact not activated byproducts
- Patterns of C3 and C4 levels indicate pathway activation
- C4 down: mild classical pathway activation
- C3 and C4 down: classical activation, formation of antibody complex
- C3 down: alternate pathway activation ^[wb lectin?]

Measuring Complement in the Diagnostic Lab
- Detecting complement in tissue biopsies
- C3 frequently detected; C1q found in diseases strongly activating classical pathway
- Laboratory looks at levels of “intact” C3 and C4 – therefore when the numbers are low this means that the
complement has been activated

Question 77

Describe the benefits and disadvantages of live attenuated vaccines

Answer 77

Active immunisation is the administration of a vaccine that elicits a protective immune response.
- killed or inactivated preparation of a pathogen
- live-attenuated pathogen
- conjugate vaccine
- subunit vaccine
- DNA vaccines
- peptide vaccines
- often requires use of an appropriate adjuvant

Live attenuated vaccines are the most effective of all vaccines.
These contains organisms cultured to reduced pathogenicity.
They retain some of the antigens of the virulent form. Examples include:
- Bacille Calmette-Guerin (BCG) ^[TB], Salmonella typhi
- Measles, mumps, rubella vaccines
- Varicella zoster
- Yellow fever

Advantages
Live, attenuated vaccines confer long lasting immunity: cell mediated, humoral and memory.

Disadvantages
However, there is a risk of restoration of virulence, or reversion, particularly in immunosuppressed or immunodeficient individuals ^[also consideration in vaccinating immunodeficient communities with BCG - IL-12 issue].
Unclear if there is an optimal number of vaccinations as eradication of natural disease occurs.

Question 78

Describe toxoid, conjugate and subunit vaccones

Answer 78

Toxoid vaccines
Some bacterial pathogens such as diphtheria and tetanus produce exotoxins.
Toxoid production involves the purification of the exotoxin, followed by inactivation with formaldehyde.

Vaccination with toxoid induces anti-toxoid antibodies capable of binding to, and neutralising the effects of, the exotoxin.
Therefore, the epitope structure of the toxoid must be maintained in order to ensure efficacy.

Conjugate vaccines
Encapsulated organisms are an important cause of morbidity and mortality in those under 2 years of age.
This is due to impaired response to polysaccharide antigens in this group.
A solution to this is conjugate vaccines.
These contain polysaccharide antigens conjugated to a carrier protein to which the immune system has already been exposed such as diphtheria, tetanus toxoids or OMPC.

The resultant immune response is T cell dependent and rapid antibody production.
It also significantly reduces morbidity associated with Hib and S. pneumoniae.

![[Pasted image 20230920181540.png]]
- T independent antigen
- cross linking with B cell receptors
- leads to differentiation into plasma cells
- no affinity maturation or memory B cells i.e. can’t mount effective response on re-exposure

![[Pasted image 20230920181558.png]]
- Conjugate vaccine = processing of carrier peptide specific T cells along with polysaccharide specific B cells
- delayed but specific
- class switching, memory, and production of high affinity antibody
- faster and better response on re-exposure

Subunit vaccines
Subunit vaccines rely on recombinant DNA technology.
Examples include HepBsAg.
The immunogenicity is compounded due to spontaneous aggregation into virus like particles.

However, failure has been demonstrated in a small group (MHC linked - HLA A1, B8, DR3) ^[receive immunoglobulin therapy].

Another example is the acellular pertussis vaccine, which is a purified subunit vaccine containing defined protein constituents prepared from B. pertussis.

Subunit vaccines: targeting antigen presenting pathways
An example is the HPV vaccine.
Virus-like particles or VLPs self-assemble when L1 protein of HPV is produced in isolation.
Vaccines comprise a mixture of types 16, 18, 6, 11; or types 16 and 18 alone.

This vaccine is highly immunogenic, and contain an aluminium salt adjuvant that precipitates VLPs, resulting in a slow release of antigen and monocyte activation ^[macrophages to site of infection that process antigen].

The second HPV vaccine contains monophosphoryl lipid A, which activates the innate immune response via TLR-4.

Both vaccines result in the production of virus-neutralising antibodies.

Question 79

Describe factors that influence commensal flora of respiraotyr tract

Answer 79

• Age, season, social factors, and mode of transmission influence commensal flora prevalence.
  
  • age: Prevalence of S. pneumoniae, H. influenzae, and M. catarrhalis decreases with age; N. meningitidis peaks in teenagers-adolescents
  • season: prevalence of many pathogens increases in winter
  • social factors: Prevalence of S. pneumoniae and H. influenzae is highest in low socioeconomic classes; Children with siblings have increased carriage of S. pneumoniae, H. influenzae, and M. catarrhalis
  • mode of transmission: carriage of pathogens requires close proximity; droplets are created by coughing, sneezing; and transmitted by person-person contact or via fomites

Question 80

DEsribe rt defence mechanisms

Answer 80

• Physical defenses include nasal hairs, irregular nasal chambers e.g. sinuses and turbinates - channel air, increase surface area to trap, mucus, ciliated epithelium (nasal cavity, sinuses, bronchi and trachea), cough reflex and epiglottic reflex, and mucociliary escalator.
• Chemical defenses include mucus secretions (phagocytes and lysozyme ^[antibacterial]), alveolar fluid(surfactant)
• Immunological defenses include alveolar macrophages and secreted antibodies (IgA).

Mucociliary Escalator
- Aids in expelling pathogens and maintaining commensal balance.
- Prevents overgrowth of upper respiratory tract commensals.
- Helps keep middle ear, mastoids, and lungs sterile.
- mucus:
- A viscoelastic gel containing water, carbohydrates, proteins, and lipids - salty and sticky
- Secreted by goblet cells of the respiratory surface epithelium and the submucosal glands
- Traps inhaled particles and microorganisms
- motile cilia:
- Hair-like projections that cycle synchronously, continually
- Move trapped particles and microorganisms in mucus toward pharynx where they’re swallowed

![[Pasted image 20230904185353.png]]
Note: the mucociliary escalator can be inhibited
- Viruses can disrupt the mucociliary escalator through:
– Direct or indirect ciliary impairment, e.g. direct damage to the ciliary system or by inducing excess mucus formation
– Secretion of enzymes that breakdown mucus
- Allows microorganisms to migrate to sterile regions - secondary bacterial infection
- Physical injury, smoking, alcohol and diabetes ^[hgih blood sugar impacts neutrophil activity] can also disrupt the mucociliary escalator

Question 81

List factors that increase risk of infection with endogenous flora

Answer 81

• Problems with drainage
  
  • Blocked sinuses or auditory tube due to viral infection or allergies
• Problems with normal physical motion
  
  • Poor cough, aspiration, intubation, paralysis
• Problems with mucociliary escalator: Poor cough, aspiration, intubation, paralysis
• specific immunocompromise or lack of immunity

Question 82

Describe streptococci

Answer 82

Streptococcus species are commensals and common causes of respiratory tract infections. (lobar pneumo if microaspiration into LRT)

Streptococci: General Characteristics

• Gram-positive cocci in chains
• Streptococcus pneumoniae classically in pairs (diplococci)
• **Facultative anaerobes

Haemolysis and Lancefield Classifications

• β-hemolytic Streptococci
  
  • S. pyogenes (Group A Streptococcus/GAS)
  • S. agalactiae (Group B Streptococcus/GBS)
  • S. dysgalactiae (Group C and G Streptococcus)
• β-, α- or γ-hemolytic
  
  • S. milleri group (Group A, C, F, G or untypable)
• α- and/or γ-hemolytic
  
  • S. pneumoniae (α-hemolytic; untypeable)
  • S. viridans group (α- or γ-hemolytic; untypeable)

S. pneumoniae as an Endogenous Pathogen

• A commensal of the URT of healthy people
  
  • More common in children (40 %) than adults (10 %)
  • Children initially colonized ~ 6 months of age
  • Highest concentration of organisms usually in nasopharynx
  • Children are **transiently colonized by different serotypes (sometimes simultaneously)
    
    • 91 known capsular serotypes
• Endogenous pathogen of the URT, can cause otitis media, mastoiditis, sinusitis
• Can disseminate into the LRT or other parts of the body, causing pneumonia, bacteremia, meningitis
• Note: Risk of developing these infections appears highest immediately after colonization *because patients have not yet produced specific antibodies to the organism

Question 83

Describe the role of epithelial and phagocytic cells in combatting encapsulated organisms

Answer 83

7. Role of Epithelial Cells

• Upregulation of Pattern Recognition Receptors (PRRs) on basal surface, allowing them to recognize bacteria that have invaded the epithelial barrier:
  
  • Basolateral surface/vacuoles: Toll-like receptors (TLRs).
  • Cytoplasm: nucleotide-binding oligomerization proteins (NODs).
• This recognition triggers an influx of inflammatory cells/lymphocytes into mucosa from the bloodstream, assisting in induction of a specific immune response to antigens of infectious agent.

8. Phagocytic Cells

• Macrophages*: Phagocytic cells that live in tissues, abundant in:
  
  • Lungs (interstitium and alveoli)
  • Connective tissue
  • Submucosal layer of the gastrointestinal tract
  • Certain blood vessels in the liver (Kuppfler cells)
  • Spleen
• Neutrophils/PMNs: Short-lived phagocytic cells in the blood (not typically found in healthy tissue).
• Dendritic cells*: Found in most tissues of the body, abundant in those that are interfaces between the external and internal environments (e.g., skin, lungs, and the lining of the GIT).
  *Form a critical link between innate and adaptive immunity by activating components of the adaptive immune system through the presentation of antigen, i.e., referred to as antigen-presenting cells (APCs).

13. Role of Phagocytes

• Recognize/bind pathogen: Step 1.
• Ingest/internalize pathogen in the phagosome: Step 2.
• Fuse phagosome with lysosome, which contains antimicrobial chemicals that destroy pathogens without the aid of the adaptive immune response: Step 3.
• Exocytosis of cellular debris: Step 4.

14. Binding of Phagocyte to Pathogen

• Directly:
  
  • Phagocyte PRRs (e.g., TLRs) bind to pathogen-associated molecular patterns (PAMPs)*.
• e.g., Gram-positive bacteria: peptidoglycan, teichoic/lipoteichoic acids, flagella.
• e.g., Gram-negative bacteria: lipopolysaccharide (LPS), flagella.
  *Relatively invariant molecular surface structures (not found in eukaryotes) that are shared by many related pathogens - can be obscured by bacterial capsules.

15. Binding of Phagocyte to Pathogen

• Indirectly:
  
  • Antibody mediated
    
    • Antibody-coated pathogen bound to Fc receptors on phagocyte surface
• Complement* mediated
  
  • Antibody-and-complement-coated pathogen bound to Fc receptors and complement receptors (e.g., CR1) on phagocyte surface.
  • *Marks foreign particles for destruction

16. Bacterial Mechanisms to Evade Phagocytosis

• prevent encounters with phagocyte: C5a peptidase and cytolytic toxins
• avoid recognition and attachment: capsules, M protein, Fc receptors
• survive within phagocyte: escape from phagosome, prevent phagosome-lysosome fusion, survive within phagosome

Question 84

Describe the roles fo B adn T cells in gneeral

Answer 84

10. Role of T-Cells

• Major population in spleen and lymph nodes.
• Typically only recognize peptide fragments presented by major histocompatibility complex II (MHCII) molecules on the surface of APCs.
• When stimulated by APCs, T-cells proliferate into:
  
  • CD4 TH1 cells produce macrophage-activating cytokines.
  • CD4 TH2 cells produce cytokines that stimulate B-cells to produce antibody.
• After a T-cell response, T memory cells persist, remembering particular antigens, thereby responding faster and more potently to re-exposure.

11. Role of B-Cells

• Present in bone marrow, other lymphoid tissues (e.g., spleen, lymph nodes, tonsils, and other mucosal surfaces), and circulate in blood and lymphatic system.
• Bind intact antigens via membrane-bound antibodies, phagocytose them (i.e., are also APCs), digest them into fragments, and display them at their cell surface via MCHII molecules.
• CD4 TH2 cells bind B-cells and produce cytokines that stimulate B-cells to differentiate into:
  
  • Plasma cells, which secrete antibodies.
  • Memory B-cells, which persist, remembering particular antigens, thereby responding faster and more potently to re-exposure.

Question 85

Describe how bacteria evade phagocytosis

Answer 85

• prevent encounters with phagocyte: C5a peptidase and cytolytic toxins
• avoid recognition and attachment: capsules, M protein, Fc receptors
• survive within phagocyte: escape from phagosome, prevent phagosome-lysosome fusion, survive within phagosome

17. Capsules Confer Resistance to Phagocytosis

• Capsules hide the bacterial targets (PAMPs) of the phagocytic receptors (PRRs).
• The phagocytic response of the innate immune system is (temporarily) inhibited.
  
  • APCs cells unable to present antigen to T-cells (via MHCII molecules).
  • Bacteria continue to replicate.
• BUT… Immune system has evolved to develop a T-cell/thymus independent (TI) response to deal with encapsulated bacteria that avoid stimulating T-cell responses.

Question 86

Describe the thymus dependent and independent responses

Answer 86

18. T-cell/Thymus Dependent (TD) Response

• Unencapsulated bacteria are susceptible to phagocytosis (provided they don’t use other evasion mechanisms).
• Proteinaceous bacterial antigens (TD antigens) can be presented to T-cells via MHCII molecules on APCs.
• Proteinacious bacterial antigens:
  
  • Referred to as TD antigens because they require recognition by T-cells to elicit an immune response.
  • Induce a long-lasting immune response due to formation of memory B-cells and T-cells.
  • Production of anti-TD antigen antibodies is delayed, but antibodies are of high affinity and of multiple isotypes (IgA, IgM, IgG1, IgG2a, IgG2b, IgG3)

19. T-cell/Thymus Independent (TI) Response

• Encapsulated bacteria are able to (temporarily) evade phagocytosis.
• Proteinaceous bacterial antigens (TD antigens) can’t be presented to T-cells via MHCII molecules on APCs.
• BUT, bacterial capsules:
  
  • Referred to as TI antigen because they don’t require recognition by T-cells to elicit an immune response.
  • TI antigens do not give rise to immunological memory.
  • TI antigens divided into TI type 1 (TI-1) and TI type 2 (TI-2) antigens based on their interaction with B-cells.
  • Humans/animals with T-cell deficiencies are able to make antibodies against bacterial antigens through a TI response.

20. TI-1 Antigens: Interactions with B-cells

• e.g. LPS, bacterial DNA in high concentrations:
  
  • Directly stimulate (i.e. inducing proliferation and differentiation of) both immature and mature B cells in the absence of T-cell help.
  • Capable of directly stimulating B cells regardless of their antigen specificity (polyclonal activation*).
  • Rapid antibody production in infants and adults (primarily IgM because TI-1 antigens do not induce isotype switching).
  • *Polyclonal B-cell activation results in a non-specific antibody response because specific TI-1 antigen binding to surface Ig not necessary (B-cell-activating moiety of TI-1 antigen sufficient to induce proliferation and antibody secretion)

21. TI-1 Antigens: Interactions with B-cells
- e.g. LPS, bacterial DNA in low concentrations:
- Directly stimulate both immature and mature B cells in the absence of T-cell help.
- Rapid antibody production in infants and adults.
- Only B cells specific for the TI-1 antigen bind enough of it to focus its B-cell activating properties onto the B-cell*.
- *Only those B cells whose B-cell receptors also specifically bind the TI-1 molecules become activated. Gives a specific antibody response to epitopes on the TI-1 antigen.

22. TI-2 Antigens: Interactions with B-cells
- e.g. bacterial capsules, viral envelopes:
- High molecular mass repetitive polysaccharide structures.
- Activate only mature B-cells (immature B-cells are inactivated by repetitive epitopes).
- Since most of the B-cells in infants are immature, they do not make antibodies against TI-2 antigens efficiently.
- Contain no intrinsic B-cell-stimulating activity.
- Simultaneously cross-link B-cell receptors of mature B-cells specific for the TI-2 antigen, resulting in production of antigen-specific antibodies.
- Rapid antibody production in individuals over 5 years of age (primarily IgM, but also some IgG- isotype switching induced by co-stimulatory signals from TH cells).

23. Only Certain Types of Mature B cells Can Respond to TI-2 Antigens

• Spleen marginal zone (MZ) B cells:
  
  • Unique set of nonrecirculating B cells in the spleen.
  • Rare at birth and take years to mature in children, also underlying the lack of antibody response in infants to TI-2 antigens.
• B-1 cells/CD5 B cells:
  
  • Autonomously replicating subpopulation of B cells.
  • Reside mainly in the pleural and peritoneal cavities, but also found in the blood and spleen.

Question 87

Describe the physilogical adaptations to hypoxia

Answer 87

Under hypoxic conditions, the human body undergoes a number of changes to adapt.

Immediately, the decrease in arterial oxygen saturation is detected by chemoreceptors located in the aortic arch and carotid body, which triggers the hypoxic ventilatory response. An increase in ventilation of up to 65% is possible (i.e. 1.65x the normal), but is limited by changes to the blood pH balance. With increased ventilation comes increased elimination of CO2 and therefore an increase in blood pH. The respiratory centre of the brainstem therefore limits any further increase in ventilation to avoid respiratory alkalosis. Over time, renal compensation and mediation of chemoreceptor sensitivity can allow up to a 5x increase in ventilation.

Over the first few days at high altitude, the body also produces hypoxia-inducible factors, which are transcription factors that upregulate the production of several genes:

• Vascular endothelial growth factor → increased vascularity of peripheral tissue
• Erythropoietin → increased production of red blood cells (polycythaemia)
  
  • Haematocrit may increase from 40% up to 60%
  • Haemoglobin may increase up to 25%
• Mitochondrial genes → increased ability of tissues to use oxygen
• Glycolytic enzymes → anaerobic metabolism → production of 2,3-bisphosphoglycerate
• Genes that increase the availability of nitric oxide → vasodilation.

Question 88

Describe the effect of 23DPG

Answer 88

• 2,3-diphosphoglycerate (2,3-DPG) is produced from 1,3-diphosphoglycerate, an intermediate product of glycolysis.
• The shape of 2,3-DPG allows it to bind to and stabilise deoxygenated haemoglobin. Therefore, this decreases the affinity of haemoglobin for oxygen, promoting oxygen delivery to peripheral tissue.
• This decrease in haemoglobin affinity for oxygen is reflected as a right shift of the oxygen-haemoglobin d

Question 89

Describe types of altitude sickness

Answer 89

If the body travels to high altitude suddenly without acclimatising, it is prone to developing acute mountain sickness (AMS), or more severely high altitude cerebral oedema and pulmonary oedema (HACE and HAPE respectively).

AMS
### Acute Mountain Sickness (AMS)

Acute mountain sickness is observed in:

• 20% of people who rapidly ascend to 2500 metres above sea level.
• 40% of people who rapidly ascend to 3000 metres above sea level.

It often manifests within the first ten hours of ascent and subsides within two days, and the presentation is highly variable. Common symptoms include:

• headache
• fatigue
• lightheadedness
• anorexia
• nausea and vomiting
• disturbed sleep with frequent awakening
• mild shortness of breath on exertion
• tachycardia.

It is important to note that in AMS, there is a lack of neurological symp

HACE
### High Altitude Cerebral Oedema (HACE)

High altitude cerebral oedema is defined by the onset of neurological symptoms. These may include:

• ataxic gait
• severe lassitude
• progressive decline of mental function and consciousness:
  
  • irritability
  • confusion
  • impaired mentation
  • drowsiness
  • stupor
  • coma.

HACE can occur between 12 hours and 3 days after the development of acute mountain sickness.

HAPE
As part of the response to hypoxia, parts of the lung will vasoconstrict to redirect blood flow to better ventilated parts of the lungs, normally facilitating ventilation-perfusion matching. However, prolonged vasoconstriction can lead to breakdown of the blood-gas barrier, leading to pulmonary oedema.

HAPE is less common than HACE, and presents with a non-productive cough initially. Other symptoms may include:

• dry cough
• decreased exercise performance
• dyspnoea at rest
• orthopnoea
• cyanosis
• tachypnoea
• tachycardia
• low grade fever
• crackles on auscultation.

Question 90

Describe response of cv and resp to altitude

Answer 90

Exercise at high altitude
Exercise at high altitude is different in many important respects from exercise at sea level.

Ventilation

Because of the decrease in air density and the lower amount of oxygen, greater ventilation is required to achieve the same oxygen uptake at high altitude. As a result, the ventilatory response to exercise is augmented at altitude compared to sea level.

For example, at 6300 m, the ventilation for a given metabolic rate is almost four times as great as at sea level

At extreme altitude, the oxygen cost of breathing during exercise may be as high as 40% of the overall metabolic rate and may result in allocation of cardiac output to respiratory muscles that could otherwise be dedicated to muscles of locomotion. Extreme dyspnea with exercise may affect the intensity and duration of exercise; with rest, dyspnea typically resolves rapidly.

Cardiovascular Response

For any given_submaximal_work rate, cardiac output and heart rate are higher during exercise at altitude compared to sea level. With acclimatization, cardiac output at submaximal workloads returns to sea-level values while the heart rate remains elevated. However,_maximal_exercise capacity and peak heart rate and cardiac output at altitude are reduced relative to sea-level values. With acclimatization, maximal exercise capacity is not restored to sea-level values over time and maximum cardiac output, heart rate, and stroke volume all remain decreased.

Question 91

Describe hypoxia and exercise

Answer 91

Hypoxia and exercise

Even exercise at sea level (where the partial pressure of inspired O2 remains stable) can induce hypoxic changes in the body. This is primarily due to limitations in the amount of oxygen consumed by the tissues as exercise intensity gets higher. The highest amount of oxygen that can be consumed by tissues is termed maximal oxygen consumption, or VO_2max_and can be determined by measuring expired O2 and CO2 response during an exercise test which increases in intensity over time.

There are various physiological changes that occur when exercising at increasing levels of intensity. These will be explored further in the following pages and later in the laboratory.

Note: hypoxia occurs even at stable altitudes because as exercise intensity increases, tissues in the body are not able to uptake and utilise inhaled O2 efficiently.

Question 92

Describe phases of pulmonary ventilation during exercise

Answer 92

Phases of pulmonary ventilation during exercise
On commencement, and while physical activity continues, there are unique phases of pulmonary ventilation that occur as depicted in the image above. They include:

• Phase I: Neural stimuli from the brain (i.e., ‘central command’), combined with feedback from active limbs, stimulate medulla to initially increase ventilation by about 20L/min.
• Phase II: There is an exponential increase in minute ventilation in order to meet metabolic demands, primarily driven by central command. Chemoreceptors likely play a role in phase IIas well, but not substantially because metabolic demand is being met, therefore there is a limited role of chemoreceptor activation.
• Phase III: Chemoreceptors play an increasingly important role to assist with ‘fine-tuning’ the ventilatory response to meet metabolic demands. If exercise intensity is low enough that metabolic demands are met, ventilatory responses plateau and remain stable. If exercise intensity increases, the ventilatory response will also increase.

Question 93

Describe compliance

Answer 93

Compliance
- Definition: Ratio of volume change to corresponding pressure change (C = ∆V/∆P) - slope of PV relationship
- Extent to which lungs expand for each unit increase in transpulmonary pressure (if enough time allowed to reach equilibrium)
- Two determinants of compliance in respiratory system:
- Lung Compliance
- Determined by lung’s elastic recoil (connective tissue, surface tension)
- Normal value: 200ml/cmH2O
- Influenced by factors: Surfactant (most important), age (shape and size), posture, size, lung volume, fibrosis (Stiff, more difficult to expand)
- Chest Wall Compliance
- Normal value: 200ml/cmH2O
- Impaired by factors affecting chest wall expansion (e.g., scoliosis, obesity ^[more tissue on chest wall,m ore pressure])
- Total Lung Compliance: Combination of lung and chest wall compliance (around 100ml/cmH2O)

Question 94

Describe stepwise treatment for asthma

Answer 94

Question 95

Describe treatment aims and options forCOPD

Answer 95

COPD Treatment Aims

• Relieve symptoms
• Prevent exacerbations
• Maximize exercise capacity
• Limit further damage
• Minimize treatment adverse effects

Smoking Cessation and Vaccines

• Smoking cessation significantly improves COPD outcomes.
• Vaccines can also provide benefits to COPD patients.

Pulmonary Rehabilitation

• Pulmonary rehab improves quality of life and exercise tolerance.
• It reduces hospital admissions and mortality.
• Minimum length of an effective
  rehabilitation program is 6 weeks
• The longer the program continues, the
  more effective the results
• Offer to all patients following hospitalised
  AECOPD and to those with mMRC ≥ 2
• Effects wear off over time

Non medical management COPD
Management – non medical
– Allergen avoidance
– Food avoidance/supplementation
– Probiotics
– Air ionisers
– Mist
– Salt caves
– Acupuncture
– Homeopathy

**Long-Term Oxygen

• Studies on these treatments’ effects and potential side effects.?

Long-Term Macrolides
1000 exacerbation
rich participants
* 1 year follow up
* FEV1 <80%
* SE – cardiovascular
events, hearing,
emergence of
resistant bacteria and
non tuberculous
mycobacteria

Roflumilast and Mucolytics

• Phosphodiesterase-4 inhibitor
• Not available in Australia
• Cannot be used with theophylline
• SE GI upset, weight loss
• Improves lung function and decreases the
  rate of moderate or severe exacerbations
  in patients with FEV 1 <50%, chronic
  productive cough and a history of
  exacerbations.

Ventilatory Support
* Consider NIV when PaCO2 >53 mmHg
(7kPa)
* Bring CO2 down (high pressures and back
up rate) this may well require hospital
admission
* ?initiate immediately after AECOPD
* Early studies suggest may worsen QoL
* Always look for (and treat) OSA

Question 96

Descrkbie sleep

Answer 96

What is sleep
Sleep is a natural, recurring state of relatively suspended sensory and motor activity in animals.
It is characterised by:
- total or partial unconsciousness
- nearly complete inactivity of voluntary muscles
It is:
- easily reversible and self-regulating
- essential for survival
- occurs in all living animals

Quality as well as quantity of sleep is essential.
Sleep disorders affect quality.

Function of sleep
Many proposed theories, with no clear answer.
- restoration
- memory
- immune
- energy conservation
- circadian homeostasis
- prevention

Different centres in the brain regulate “wake” and “sleep”.

• Wake
  
  • Reticular formation
• Sleep
  
  • Thalamic relay ^[i.e. not a uniform event]

When awake, brain waves are fast and have low amplitude.
As sleep gets deeper, waves get slower and deeper, with higher amplitudes.
There are four stages of sleep. 4 is the deepest.

Note that REM is an active stage of sleep.

Different stages have different functions:
- deep sleep has a pruning function
- REM aims to refresh networks

Drivers of sleep
- Sleep debt
- Circadian “body clock”

Sleep debt
- Paid with slow wave sleep
- Mostly first half of the night

Body clock
- Regulates cycle of sleep
- Influences REM sleep
- REM mostly second half
- note also that the duration of REM increases in the second half

Question 97

List OSA risk factors

Answer 97

Risk factors for OSA
- Craniofacial
- Nose - resistance
- Mouth - large tongue, soft palate, retrograde mandible and overbite
- Jaw
- Tonsils
- General
- Muscle tone - impacted by alcohol and hypothyroidism, obesity, especially central obesity
- Overnight testing
- Polysomnography

Question 98

Describe SDB

Answer 98

Cardiovascular Pathophysiology of SDB (Sleep Disordered Breathing)
- Intermittent hypoxia
- Arousal response
- Oscillation of:
- systemic and pulmonary arterial blood pressures
- Heart rate
- Cardiac function

Consequences of SDB (Sleep Disordered Breathing)
Consequences can be the result of multiple pathways:
- Arousal - sleep disruption
- Sympathetic NS stimulation
- Hypoxaemia
- Deox-reox flux - reactive oxygen species
- Cardiovascular effects
- Neurohormonal effects
- Airway, chest pump effects
- Inflammatory effects

Question 99

Describe what causes OSA

Answer 99

Causes OSA?
When airways collapse
Airway obstruction usually occurs in oropharynx i.e. is retropalatal and retroglossal

![[Pasted image 20230922130315.png]]

OSA is caused by:
- Factors that Increase Compliance of Tube
- ![[Pasted image 20230922130407.png]]
- a reduction in transmural pressure (Plumen - Ptissue)

Factors that Increase Compliance of Tube
1. Reduction in Longitudinal Tension of the Tube
- Reduction of lung volume (e.g., due to central obesity)
2. Suppression of Pharyngeal Muscle Activation (Reduces Airway Tone)
- Alcohol, sleep deprivation, anaesthesia
- note that some people only have it with alcohol consumption

A Reduction in Transmural Pressure (P tm) is Due to
A. Increase in Surrounding Tissue Pressure (P tissue) or
B. Decrease in Intraluminal Pressure (P lumen)

Increase in Surrounding Tissue Pressure
- Rigid box too small: bordered by mandible (anterior and lateral walls) and cervical spine (posterior wall)
- neck and jaw posture also influence the size of the box
- neck flexion closes airway
- neck extension opens it
- jaw opens slightly : increases size of box
- jaw opens wide: decreases size of box by moving genu of mandible posteriorly

Too Many Other Things in the Box
- Soft palate (muscle and fat)
- Tongue (muscles and fat)
- Muscles (posterior constrictors and oropharyngeal muscles)
- Tonsils (lymphoid tissue)
- Adipose tissue (parapharyngeal fat pads)
-
- Note: Edema (e.g. due to inflammation and tissue swelling) resulting from OSA can therefore make OSA worse

Box Too Small
- Rigid box =
- Mandible (anterior and lateral walls)
- Cervical spine (posterior wall)
- Neck and jaw posture also influence the size of the box
- Neck flexion – closes airway
- Neck extension - opens it
- Jaw open slightly – increases the size of the box
- Jaw open wide – decreases the size of the box by moving the genu of the mandible posteriorly

Position of Tongue and Soft Palate
- Affected by gravity and surface tension
- Mouth opening - decreases mucosal surface tension, thus freeing mucosal attachment of tongue and soft palate, allowing tongue and soft palate to move posteriorly
- Sleeping supine causes gravity to pull the tongue and soft palate posteriorly

Obesity and OSA
![[Pasted image 20230922130715.png]]

Decrease in Intraluminal Pressure
- Nasal obstruction
- Airway obstruction due to
- Loss of energy due to work done in overcoming flow resistance, and
- The Bernoulli effect
- Conversion of energy from static to kinetic due to increased velocity of airflow when the lumen size decreases

Question 100

List conditions that exacerbate and are exacerbated by OSA

Answer 100

Illnesses That Can Exacerbate OSA
- Anything that causes weight gain (e.g., hypothyroidism, or conditions that reduce mobility and ability to exercise), or requires medications that cause weight gain (e.g., corticosteroids, some anti-epileptics, some anti-psychotics)
- Hypothyroidism also causes myxoedema which can exacerbate OSA. It also results in daytime symptoms that can be similar to those resulting from OSA.
- Anything that causes nasal obstruction (e.g., hayfever)
- Anything that results in craniofacial abnormality

Conditions That Can Increase the Adverse Health Risks of OSA
- Conditions that result in nocturnal hypoventilation can cause worse overnight O2 desaturation and increase the risk of pulmonary hypertension (e.g., COPD, Obesity Hypoventilation Syndrome)
- Hypertension, diabetes, elevated cholesterol increase the cardiovascular risks associated with OSA

Conditions That May Be Exacerbated by OSA
- Afib
- Hypertension
- Obesity
- GORD
- CVA
- IHD and cardiac failure
- Depression (this may, however, also cause daytime sleepiness)

Question 101

List common URTI and LRTI causes and briefly describe their morphology

Answer 101

7. Name 3 bacterial microbes which commonly cause URTI and LRTI, and describe their gram stain appearance and organization

Step pneumoniae – gram +ve diplococci
Step pyogenes – gram +ve cocci in chains
Haemophilus influenzae – Gram –ve coccobacilli
Neisseria meningiditis – gram –ve diplococci
Moraxella catarrhalis – gram –ve diplococci

Question 102

Describe flow

Answer 102

• Flow Definition: Substance passing point per unit time
• Flow governed by Ohm’s Law
• Two main types of flow:
  
  • Laminar Flow: Straight, unbranched tube; fastest center flow ^[i.e. in middle of tube]
  • Turbulent Flow: Irregular or branched tubes; eddies, higher resistance
• n.b. Transitional Flow: Mixture of laminar and turbulent
• in lung: mix of laminar, turbulent and transitional
• Flow Equation: Flow = Pressure difference (pressure coming in - going out) / Resistance
• Resistance Formula: R = 8nl / πr ^4
  
  • n = viscosity ^[usually fixed]
  • l = length ^[usually fixed]
  • r = radius
    
    • radius most important e.g. half radius = 16 fold change ^[relevance in pathology]
• Laminar Flow
  
  • ‘series of concentric cylinders sliding over each other’
  • Faster in center, slower at edge
  • ‘even front’
• Turbulent Flow
  
  • higher flow rates/flow through branched or irregular tubes
  • causes concentric circles to breakdown
  • flow becomes small currents or eddies, higher friction
• Reynolds Number (Re) - describes tendency towards turbulent flow
  
  • Dimensionless number indicating likelihood of turbulent flow
  • Re = ρDv / η
  • ρ = Gas density
  • D = Tube diameter
  • v = Flow velocity
  • η = Viscosity of gas
    
    • > 2000 associated with turbulent flow