Resp Flashcards
List non-neoplastic and neoplastic lesions of lung
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
Describe malignant neoplasms of lung
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
Describe sclc
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
Describe squamous celll lung cancer
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
Describe adenocarcinoma
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
Describe large cell lung ncancer
associations
Diffuse and undifferentiated, anaplastic
pathology
Peripherally located, Histology = giant cells, spindle cells
treatment/prognosis
Metastasis early and distant
Describe treatment for lung cancer
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)
Define diffusion and describe the determinants
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
Describe ventilation and issues of ventilation
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
Describe perfusion and issues of perfusion
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.
Describe the balance of pressure that keeps the lung open/describe pressure, volume and flow changes in respiration
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.
Describe FRC
- 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
Descrive FV loops
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
Describe work of breathing
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
Describe the controls of respiration
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
- type I Glmous cells: have oxygen sensitive potassium channels, which close if pO2 decreases, thus increasing pCO2 sensitivity
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
Describe the dynamic nature of the FV loop
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
Describe changes to breathing work in disease
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
Describe V/Q mismatches
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
Describe changes to lung in acidosis and alkalosis
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
Describe DLCO
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
Describe 6mwt
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
Describe body plethysmography
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
Compare and contrast type 1 and 2 repiratory failure
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.
HIHIIHI
Describe transport and distribution of O2 and CO2
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
Compare and contrast obstructive and restrictive disease
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.
Describe investigations to distinguish between obstructive and restrictive disease
- spiromtery
- body plethysmography
- iamging
- ## bronchodilator test
Describe the stages of bacterial pneumonia
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.
List pathologies of restrictive diseases
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
Describe the histology of asthma
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
Describe the pathophysiology of asthma
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
Interpret spirometry
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.
Distinguish between respiratory acidosis and alkalosis
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
List cardiac and respiraoty causes of dyspnoea
- 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,
List types of pneumonia and briefly describe them
- Bronchopneumonia
o Patchy consolidation of the lung. - 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.
Distinguish between lung volumesand capacities
- Static does not change
- Dynamic can change
- Capacity = two or more volumes
List and describe pathogens causing pneumonia
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]
Describe complications of bacteria pnumonia
- 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.
Describe the radiological appearance of pneumonia
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
Describe corticosteroids
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
Describe corticosteroids
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
Describe FV curves in disease
Describe Bohr effect
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.
Describe paranasal sinuses
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
Describe the thymus dependent and independent responses
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.
Describe stepwise treatment for asthma
