1
Q
Describe the pathophysiology of Asthma
A
-Normal airway with bronchial epithelium, some matrix and some smooth muscle under it
-Allergen sensitises airway — causes inflammation and airway remodelling
- Recruitment of inflammatory cells into airway (mostly eosinophils)
- structural changes in airway is increase in goblet cells which produce mucus
-Amount of matrix increases too and amount + size of smooth muscle cells increase
2
Q
what genes are expressed according to GWAS study of asthma?
A
GSDMB
IL33
3
Q
How does type 2 immunity reaction come about in allergic asthma?
A
Allergen exposure - lung dendritic cells – MHC II – Mediastinal lymph nodes — Naive T cells – T helper cells - IL 4, 5, 13
4
Q
What does il 4 do?
A
B cellls differentiate and produce IgE cells
5
Q
What does il 5 do?
A
Eosinophil recruitment and survival
6
Q
What does il 13 do?
A
Mucous secretion
7
Q
How do we test for allergic sensitisation? (2)
A
Blood test for specific IgE antibodies
Skin prick test
8
Q
How do we test for eosinophil levels?
A
- Blood eosinophil count when stable → ≥300 cells/mcl is abnormal
- Induced sputum eosinophil count: ≥2.5% eosinophils is abnormal
- Exhaled nitric oxide-
9
Q
What objective tests are done to diagnose asthma? (3)
A
- Reversible airway obstruction- bronchodilator reversibility ≥12%
- Airway obstruction on spirometry- FEV1/FVC ratio <0.7
- Exhaled NO (FeNO) >35ppb (children), >40ppb (adults)
10
Q
Reduce airway eosinophilic inflammation of asthma- how? (2)
A
- Inhaled corticosteroids- target and reduce eosinophilic inflammation
- Leukotriene receptor antagonists- can reduce type 2 inflammation
11
Q
Acute symptomatic relief of asthma- how? (2)
A
- Beta-2 agonists (smooth muscle relaxation)
- Anticholinergic therapies (smooth muscle relaxation)
12
Q
How does anti-IgE antibody therapy work?
A
- Reduction in serum IgE over time means the therapy may not need be used indefinitely
- Binds and captures circulating IgE- prevents its interaction with mast cells and basophils to stop allergic cascade
-IgE production can decrease with time when patients given anti-IgE Ab
- Binds and captures circulating IgE- prevents its interaction with mast cells and basophils to stop allergic cascade
13
Q
What is Omalizumab?
A
- The commonly used anti-IgE antibody given as subcutaneous injections
- Is very expensive
- Is effective at reducing exacerbations compared to placebo
When is it used?
Severe, persistent allergies (IgE mediated) asthma in patients ≥6 years who need continuous or frequent treatment with oral corticosteroids
Have to have optimised standard therapy with good adherence with no response
- What serum IgE level is it prescribed for?
Total serum IgE between 30-1500
14
Q
Mepolizumab
A
- Anti-IL5-antibody
- Reduces IL-5 effect, reducing eosinophilic inflammation in severe eosinophilic asthma
- Licensed for adults and children ≥6
- When is it trialled?
Blood eosinophils ≥300 cells/mcl in the last 12 monthsAt least 4 exacerbations requiring oral steroids in the last 12 monthsFor 12 months- 50% reduction in attacks, then continue
15
Q
Dupilumab
A
Anti IL4 / IL13 receptor
16
Q
Define respiratory failure
A
Syndrome of inadequate gas exchange due to dysfunction of ≥1 components of respiratory system
Respiratory system:
Nervous
Muscular
Pulmonary
17
Q
According to Berlin’s Classificatio. how do you identify ARDS?
A
- Timing: Within 1 week of known clinical insult or new or worsening respiratory symptoms
- Chest Imaging: Bilateral opacities - not fully explained by effusions, lung collapse
- Origin of odema: Not fully explained by cardiac failure or fluid overload - echocardiogram
- Oxygenation:
Severe <100
Moderate 100 -200
Mild 200 - 300
18
Q
Explain how perfusion and ventilation changes across the lung?
A
Ventilation: Not impacted by gravity so aveoli at the apex of lung show less compression , larger diameter and less compliant. Greater pleural pressure. Less ventilation
Perfusion: Impacted by gravity so at the base of the lung more compression, more blood vessels, more perfusion. Higher intravascular pressure, higher flow rate, less resistance
19
Q
How would you describe the ventilation perfusion matching according to zones of the lung?
A
Zone 1- Alveolar pressure is higher than arterial and venous
2- arterial pressure is higher than alveolar and venous
3- arterial and venous are higher than alveolar
20
Q
Complaince vs elastance
A
Compliance is the volume per unit pressure- ease of stretching
AV/AP
Elastance is the amount of pressure required to distend by a volume- resistance to being stretched
-The elastic recoil of the chest and lung tissue
AP/AV
21
Q
What is the formula for minute ventilation and when is it used?
A
Tidal volume (L) x Breaths/min = L/min
Gas entering and leaving lung
22
Q
What is the formula for alveoli ventilation and when is it used?
A
(Tidal volume - dead space) x breath per minute
Gas entering and leaving the alveoli
23
Q
Type 1 or Hypoxemic resp failure- what does this mean?
A
- Failure of oxygen exchange
- PaO2 <60 at sea level
- Increased shunt fraction (QS/QT)
- Due to alveolar flooding in heart/CVD failure patients
- Hypoxemic refractory to supplemental oxygen
24
Q
- Increased shunt fraction (QS/QT)- what does this mean?
A
More blood transported through lungs without taking part in gas exchange
25
Causes of Type I respiratory failure
- Collapse of lobe
- Aspiration
- Fibrosis
- Pulmonary oedema
- Pulmonary embolism
- Pulmonary hypertension
26
Type 2 or Hypercapnic resp failure- what does this mean?
- Failure to exchange or remove CO2
- Decreased alveolar minute ventilation
- Dead space ventilation
27
Causes of Type 2 respiratory failure
- Nervous system issues
- Neuromuscular issues
- Muscle failure- muscles too tired to maintain tidal volume
- Airway obstruction
- Chest wall deformity
28
Type 3 or perioperative failure- what does this mean?
- Increased atelectasis (collapse of entire lung or lobe) due to low functional residual capacity (FRC) with abnormal abdominal wall mechanics
- You can have hypoxemia or hypercapnia
29
How do we prevent type 3 respiratory failure?
- Anaesthetic or operative technique
- Posture
- Incentive spirometry
- Analgesia
- Attempts to lower intraabdominal pressure
30
Type 4 resp failure aka shock- what does this mean?
- This happens in intubated and ventilated patients during shock (septic/cardiogenic/neurologic)
- Poor perfusion of the lung so gas can’t come into blood
Optimise ventilation improve gas exchange and to unload the
respiratory muscles, lowering their oxygen consumption
31
What are the effects of the ventilator on the left ventricle and right ventricle in type 4 respiratory failure?
Reduces LV afterload, Increased RV pre and after load
32
What occurs in acute lung injury?
The complex interaction- the lung can be injured from either direction
From the lung or to the lung.
Within the lung infection will lead to macrophage and neutrophil activation, triggering release of cytokines such as TNF and IL-6, IL-8 for example.
These result in activation of a cascade of inflammatory responses which are key to resolution of lung injury but may often become disruptive.
In additional to the biological consequences at the receptor level, these responses drive inflammation and alveolar fluid leak across the endothelium.
As the endothelium becomes oedematous this secondarily impairs gas exchange.
33
What in vivo evidence do we have for acute lung injury? (5)
- TNF signalling implicated- reduced injury of alveolar lung injury by blocking TNFR-1 signalling pathway with Ab or using TNFR-1 knockouts
- Macrophage activation occurs in alveolar space and neutrophil lung migration also occurs
- DAMP release (commonest for lung are HMGB-1 and RAGE)
- Cytokines are released e.g. IL-6, 8, IL-1B, IFN-gamma (this is important for viral response and T cell differentiation)
- Cell death- there is necrosis in lung biopsies, and also apoptotic mediators e.g. FAS, FAS-I and BCl-2
34
Therapeutic intervention for ARDS
TREAT UNDERLYING CONDITIONS
Inhaled therapies
Bronchodilators
Pulmonary vasodilators
Steroids
Antibiotics
Anti-virals
Drugs
Pyridostigmine
Plasma exchange
IViG
Rituximab
RESPIRATORY SUPPORT
Physiotherapy
Oxygen
Nebulisers
High flow oxygen
Non- invasive ventilation
Mechanical ventilation
Extra-corporeal support
MULTIPLE ORGAN SUPPORT
Cardiovascular support
Fluids
Vasopressors
Inotropes
Pulmonary vasodilators
Renal support
Haemofiltration
Haemodialysis
Immune therapies
Plasma exchange
Convalescent plasma
35
How does the pressure-volume loop change for ARDS from normal?
- ARDS lung is much stiffer so volume is reduced and more pressure is used at the top to get very little gain in volume increase
- Lung can drop below lower inflection point leading to lung collapse
- We try to keep end expiratory pressure so that lung remains open and that we open lung just enough- we don't push it too hard with too much pressure that would cause damage and inflammation and oedema and alveoli will stop working
36
How most commonly gets lung cancer? (4)
- Age- peak is 75-90
- Sex- M>F
- Lower socioeconomic status
- Smoking history- duration, intensity, when stopped
37
What other than smoking are causes of lung cancers?
- Passive smoking is 15% of these
- Chronic lung diseases (COPD, fibrosis)
- Asbestos- exposure increases risk up to x2
- Radon e.g. silver miners in Germany in 1800s
- Indoor cooking fumes- wood smoke, frying fats
- Air pollution
- Familial/genetic- several loci identified
38
Pathogeneis of lung cancer
Inhaled carcinogens interact with the epithelial of the upper and lower airways
This leads to the formation of DNA adducts (pieces of DNA covalentaly bonded to cancer causing chemicals)
Persisting DNA adducts/misrepaired adducts result in a mutation and can cause genomic alterations.
39
What are the 4 main types of lung cancer?
Squamous cell carcinoma (~30% of cases).
– originating from bronchial epithelium; centrally located
Adenocarcinoma (~40%)
– most common from 1980s onwards – low tar cigarettes, inhaled more deeply / retained longer
– originating from mucus-producing glandular tissue; more peripherally-locate
Large cell lung cancer (~15%)
heterogenous group, undifferentiated
Small cell lung cancer (~15%)
originate from pulmonary neuroendocrine cells
highly malignant
40
Common oncogenes impacted in lung cancer
epidermal growth factor receptor (EGFR) tyrosine kinase
-15-30% of adenocarcinoma
-more so in women, Asian ethnicity, never-smokers
anaplastic lymphoma kinase (ALK) tyrosine kinase
- 2-7% of non-small cell lung cancer
-especially in younger patients and never smokers
c-ROS oncogene 1 (ROS1) receptor tyrosine kinase
1-2% of non-small cell lung cancer
especially in younger patients and never smokers
BRAF (downstream cell-cycle signalling mediator)
1-3% of non-small cell lung cancer
especially in smokers
41
Key symptoms of lung cancer
Cough
Weight loss
Breathlessness
Fatigue
Chest pain
Haemoptysis
42
Signs of lung cancer
Clubbing, Cachexia, Superior vena cava obstruction (Pemberton’s sign), Horner's syndrome
43
Imaging in lung cancer
Chest X ray
Staging CT ( chest and abdomen)
PET - CT occult metastsis
44
Biopsy in lung cancer
Bronchoscopy - central and segmented airway tumours
Endobronchial ultrasound and transbronchial-needle aspiration of mediastinal lymph nodes (EBUS [TBNA])
To stage mediastinum +/- achieve tissue diagnosis
CT-guided lung biopsy
To access peripheral lung tumours
45
Staging and classification of lung cancer
T1- T4
<3, 3 -5 , 5- 7 (invading a little a lot) , 7+ ( invading a lot)
N0 - N3
Ipsi Ipsi Contra lung mediatinal lung
M0 - M1c close, far but one, far but more
Could also be staged as
Early vs locally-advanced vs metastatic
46
Determinants of lung cancer treatment
Patient fitness
Cancer histology
Cancer stage
Patient preference
Health service factors
47
Patient fitness – WHO performance status
0 – Asymptomatic (Fully active, able to carry on all predisease activities without restriction)
1 – Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. For example, light housework, office work)
2 – Symptomatic, up and about >50% of waking hours(Ambulatory and capable of all self care but unable to carry out any work activities)
3 – Symptomatic, confined to bed or chair >50% of waking hours (Capable of only limited self-care)
4 – Completely disabled (Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair)
5 – Death
48
Which group according to WHO classification of patient fitness is qualified for radical treatment?
0 – Asymptomatic (Fully active, able to carry on all predisease activities without restriction)
1 – Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. For example, light housework, office work)
2 – Symptomatic, up and about >50% of waking hours(Ambulatory and capable of all self but not able to carry out work)
49
What sections of the lung can be taken out and what are they called?
Wedge resection- small section of lung tissue and a bit of healthy tissue
Segmental resection - large section of lung tissue but not yet a full lobe
Lobectomy - lung
Pneumonectomy - one out of lung pair
50
What two ways can lung be accessed in surgery?
Open thoracotomy
Video assisted thorascopic surgery
51
Radical radiotherapy:
Who is it good for?
How does it work?
Alternative to surgery for early stage disease
Particularly if comorbidity
Stereotactic ablative body radiotherapy (SABR)
- Technique of choice
- High-precision targeting, multiple convergent beams
52
First line for metastatic NSCLC with mutation
Anti- EGFR
Anti- ALK
Anti - ROS1
improvements in progression-free survival, modest overall survival vs standard chemotherapy
Side effects
generally well-tolerated (tablets)
rash, diarrhoea, and (uncommonly) pneumonitis
53
First line for metastatic NSCLC with no mutation (and PDL1 ≥50%)
Pembrolizumab
improvements in progression-free survival and overall survival vs standard chemotherapy
generally well-tolerated
Immune-related side-effects in 10-15%
54
First line for metastatic NSCLC with no mutation and PDL1 ≤50% (in combination with immunotherapy)
Cytotoxic chemotherapy
Target any rapidly dividing cells
Platiunum-based regimens
Frequent: fatigue, nausea, bone marrow suppression, nephrotoxicity
Quality of life poorly evaluated in trials; no evidence for improvement
55
Management of locally advanced disease (involving thoracic lymph nodes)
Surgery + adjuvant chemotherapy
Radiotherapy + chemotherapy +/- immunotherapy
BRS missed out
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