Respiratory System Flashcards
(164 cards)
1
Q
How is a negative pleural pressure established?
A
The lung elastic recoil is inward while the chest wall elastic recoil is outwards.
2
Q
What is elastic recoil?
A
Having the property of being able to spring back and return to the original shape after being distorted.
3
Q
How does gas move in to the alveoulus?
A
Atmospheric pressure is greater than alveolus pressure.
Inspiratory neural activity from the brain draws the diaphragm down and contracts the external intercostal muscles to pull ribs up and out. This causes the negative pressure difference in the alveolar space.
Inspiratory time < expiratory time.
4
Q
How to gas move out of the alveolus?
A
Alveolar pressure is greater than atmospheric.
No inspiratory neural activity so lung does elastic recoil inwards. This is passive.
Inspiratory time < expiratory time.
5
Q
What happens during large/forced expiration?
A
Diaphragm is pushed upwards as abdominal muscles contract. Internal intercostals contract, pushing chest wall inwards by moving ribs downwards.
6
Q
What causes SOBOE (shortness of breath on exertion) in COPD?
A
Decreased lung elastic recoil, Obstructive airways disease, Static and dynamic hyperinflation, Inability to efficiently increase tidal volume.
7
Q
Where is voluntary control of breathing controlled?
A
The cortex.
Removal of cortex + upper pons leads to slow gasping breaths.
8
Q
Where is autonomic breathing controlled?
A
The pons, medulla and spinal cord.
Removal of cortex + upper pons leads to slow gasping breaths.
Removal of pons causes return to rhythmic breathing.
Removal of medulla leads to breathing stopping.
9
Q
How is rhythmic breathing generated?
A
Medullary neurones control rhythmic breathing: ventral respiratory group (VRG) and dorsal respiratory group (DRG).
Inspiratory neurones activate expiratory neurones and cause expiration (contraction of diaphram and intercostals).
Expiratory neurones inhibit inspiratory neurones.
So a cycle of rhythmic breathing commences.
10
Q
What is the effect of large inspiration on the rhythm of breathing?
A
Controlled by medullary neurones: ventral respiratory group (VRG) and dorsal respiratory group (DRG).
Inspiratory neurones cause a large activation of expiratory neurones. This causes contraction of expiratory muscles and inhibits inspiratory neurones.
Leads to a rhythm/cycle.
11
Q
What are the feedback inputs to the respiratory rhythm generator?
A
Lung receptors (afferent fibres carried in vagus nerve):
Slow adapting receptors,
Rapidly adapting receptors,
C-fibre endings.
Chemoreceptors:
Central chemoreceptors,
Peripheral chemoreceptors.
12
Q
What is the effect of lung receptor activity on the pattern of breathing?
A
If vagal nerves are cut, volume increases and rate decreases (slow, deep breaths).
If vagal nerves are stimulated, volume decreases and rate increases (fast, shallow breaths).
Slowly adapting receptors respond to a stimulus and then keep firing.
Rapidly adapting receptors respond to a stimulus and then slow down as they get used to it.
13
Q
What are slowly adapting lung receptors (SARs)?
A
AKA stretch receptors.
Mechanoreceptors situated close to airway smooth muscle.
Stimulated by stretching of airway walls during inspiration.
Help initiate expiration and prevent over inflation of the lungs.
Initiate Hering-Breuer inflation reflex (prolonged inspiration produces prolonged expiration).
Afferent fibres are myelinated.
14
Q
What are Rapidly adapting lung receptors (RARs)?
A
AKA irritant receptors.
Located in airway epithelium.
Primarily a mechanoreceptor (like SARs) so respond to rapid lung inflation.
Respond to chemicals (e.g.histamine), smoke, dust.
RARs in trachea and large bronchi initiate cough, mucus production, bronchoconstriction.
Afferent fibres are myelinated.
15
Q
What are the C-fibre endings in the lungs?
A
Unmyelinated nerve fibres that provide sensory input from airway and lung structures.
Stimulated by increased interstitial fluid (oedema) and various inflammatory mediators (histamine, prostaglandins, bradykinins). Linked to vagus nerve.
Bronchial C-fibres Endings in the airway epithelium; and;
Pulmonary C-fibres (juxtapulmonary capillary receptors, J-receptors) Endings close to the pulmonary capillaries.
16
Q
What is the chemoreceptors response to arterial O2 and CO2?
A
Arterial pH is driven by CO2.
For central, has to travel across blood-brain barrier. Central chemoreceptors on surface of medulla detect [H+] once pCO2 has dissociated and sends info to medullary rhythm generator.
Peripheral chemoreceptors have a FAST response to:
Arterial pO2, arterial pCO2, and arterial [H+].
Central chemoreceptors have a SLOW response to:
Arterial pCO2, only.
Sensory nerve is the vagus, motor nerve is the phrenic.
17
Q
What is the ventilatory response to CO2?
A
As pCO2 increases in normoxia (normal O2), minute ventilation also increases.
In hypoxia (low O2), minute ventilation will be greater than in normoxia.
In hyperoxia (high O2), minute ventilation will be less than in normoxia.
18
Q
What is the ventilatory response to hypoxia (low O2)?
A
Hypercapnia (raised pCO2).
19
Q
How is breathing altered due to sleep?
A
Midbrain neural activity stimulates breathing during wakefulness (“wakefulness drive to breathe”). Neural activity (cortex, pons, medulla) also regulates muscles in the UPPER AIRWAY (i.e. above the trachea).
During sleep:
Respiratory drive decreases (loss of wakefulness drive) causing reduction in metabolic rate and reduced input from higher centres such as pons and cortex;
Loss of tonic neural drive to upper airway muscles.
Consequences of loss of wakefulness drive is that patients with impaired ventilation (e.g. muscle weakness, severe lung disease, neuropathy or spinal deformity) first develop respiratory failure (raised arterial CO2) during sleep.
20
Q
What is muscle airway muscle activity?
What happens to it during sleep?
A
Phasic: contraction of upper airway muscles, opening of upper airway, facilitates inward airflow, (similar to activity in diaphragm/external intercostals which generate inspiration).
Tonic: continuous background activity, tends to maintain patent airway, varies with state of alertness, (similar to activity in skeletal muscles which maintain posture).
During sleep: loss of tonic activity to upper airways, airways collapse (obstruct) to give cessation of breathing (= apnoea).
21
Q
How does partial pressure of oxygen affect gas exchange?
A
At equilibrium, partial pressure of gas in solution equals partial pressure of gas above liquid. But most oxygen is carried by haemoglobin rather than dissolved.
Gas exchange is driven by partial pressure. Partial pressure of oxygen in the alveolus equals the partial pressure in the blood draining the alveolus.
However, due to shunting and dead space, there is no apparent equilibrium if we consider the lung as a complete unit - partial pressure of O in arterial blood is lower than the alveolus.
22
Q
Why is the pO2 of arterial blood lower than we might expect?
A
Anatomical shunts:
A small amount of arterial blood doesn’t come from the lung (Thebesian veins);
A small amount of blood goes through without seeing gas (bronchial circulation).
Physiological shunts (decrease V {ventilation}) and alveolar dead space ( decreased Q {perfusion}):
Not all lung units have the same ratio of ventilation (V) to blood flow (Q);
V/Q mismatch.
23
Q
What is physiological dead space?
A
Anatomical dead space represents the conducting airways where no gas exchange takes place.
Alveolar dead space represents areas of insufficient blood supply for gas exchange and is practically non-existent in healthy young but appears with age and disease.
Physiological dead space = anatomical dead space + alveolar dead space.
24
Q
What does the ventilation to perfusion ratio mean?
A
V/Q
If ventilation = perfusion then will get perfect gas exchange (shunting aside…).
In the lung, naturally have V/Q mismatch with less blood and air going to the top of the lung
25
What is 'normal' V/Q mismatch?
Zone 1 - top of the lung:
Less airflow and blood flow but V>Q, so increased V/Q, and pO2 is higher.
Zone 2 - middle of lung:
V/Q is normal.
Zone 3 - bottom of lung:
More ventilation and more blood flow but V
26
Why do patients become hypoxaemic?
Hypoventilation:
Cause of low oxygen levels as not enough oxygen is being provided for gas exchange.
Ventilation perfusion (V/Q) mismatch (pathological vs. physiological):
In healthy lungs the physiological V/Q mismatch generally cancels itself out. But in disease, it may become more apparent, and lung diseases can cause additional V/Q mismatch leading to gas exchange problems.
Or both of the above.
27
What causes hypoventilation?
Respiratory: restrictive vhest physiology, pulmonary hypertension, hypoxemia/hypercapnia;
Central Nervous System: decreased central respiratory drive;
Airway: potential difficult airway, sleep apnea;
Cardiovascular: coronary artery disease, congestive heart failure;
Others: difficult vascular access, difficult positioning.
28
What causes failure of the ventilatory pump?
Won’t breathe: control failure:
Brain failure to command e.g. drug overdose;
Can’t breathe - broken peripheral mechanism:
Nerves not working e.g. spinal injury,
Muscles not working e.g. muscular dystrophy,
Chest can’t move e.g. severe scoliosis,
Gas can’t get in and out e.g. asthma/COPD.
29
What happens to CO2 levels in hypoventilation?
Oxygen levels go down in hypoventilation.
During normal ventilation CO2 diffuses out of blood into alveolus following a partial pressure gradient.
CO2 is mostly dissolved in blood rather than bound to haemoglobin.
If there is lower ventilation, then CO2 accumulates in the alveolar space meaning less can be removed from the blood. So hypoventilation leads to increased pCO2.
30
What causes V/Q mismatch?
Conditions that thicken the alveolar wall or narrow and block small airways,
Lung infection such as pneumonia (fluid in alveoli),
Bronchial narrowing such as asthma and COPD (although they can also progress to hypoventilation and type 2 resp failure),
Interstitial lung disease,
Acute lung injury
31
What causes V/Q mismatch in pneumonia?
Pneumonia causes inflammation and damage in the small airways and alveoli. Airways narrow and fluid builds up in alveoli.
Results in hypoxaemia because blood does not come into contact with adequate O2. CO2 will also increase but this does not impact overall CO2 levels in blood.
32
What happens to arterial O2 In V/Q mismatch?
Blood leaving areas of low V/Q ratio has low PaO2 and high PaCO2.
High PaCO2 stimulates ventilation.
‘Extra’ ventilation goes to areas of normal lung and areas with high V/Q ratio. But extra ventilation can’t push O2 content much higher than normal.
Blood from both areas mixes but cannot overcome the low oxygen level.
Hyperventilation: high PaO2 but content not high.
Low V/Q ratio: low PaO2 and content.
33
What happens to arterial CO2 in V/Q mismatch?
Blood leaving areas of low V/Q ratio has low PaO2 and high PaCO2.
High PaCO2 stimulates ventilation. ‘Extra’ ventilation goes to areas of normal lung and areas with high V/Q ratio so get blood with low CO2.
Blood from both areas mixes so overall CO2 is normal.
Low V/Q ratio: high PaCO2 and content.
Hyperventilation: low PaCO2 and content.
34
What is type 1 respiratory failure?
PaO2 is low but PaCO2 is NOT high.
V/Q mismatch is the main problem.
Common causes: pneumonia, (pulmonary embolism), acute severe asthma, COPD.
35
What is type 2 respiratory failure?
PaO2 is low and PaCO2 is high.
Ventilatory failure (hypoventilation) is main feature.
Common causes: opiate toxicity, severe COPD (acute/chronic), acute severe asthma, Pulmonary Oedema in acute Left Ventricular failure.
36
How do we treat Type 1 respiratory failure?
Give oxygen - this is a short-term life saving measure.
The fundamental problem is inadequate gas exchange. Improve gas exchange by treating underlying cause.
In some cases mechanical ventilation is required.
37
How do we treat Type 2 respiratory failure?
Give oxygen - controlled in COPD patients with chronic respiratory failure.
Treat the underlying cause to reverse hypoventilation e.g. bronchodilators for acute asthma or opiate antagonists for overdoses.
Support ventilation: non-invasive ventilation/invasive ventilation.
38
What are the physiological roles of hydrogen ions?
Needed in mitochondria, protein conformation/function, and metabolism.
39
How is hydrogen ion concentration regulated?
Human hydrogen ion concentration tightly regulated.
Homeostasis achieved through production ~ excretion and buffering.
40
How are hydrogen ions produced?
Carbon dioxide: 20000 mmol/d, produced by tissue respiration, lung excretion.
Lactic acid: 1300 mmol/d, produced by glycolysis, oxidation or gluconeogenesis.
Ketoacids: 400 mmol/d, produced by ketogenesis, oxidation.
Urea synthesis: 1140 mmol/d, produced by ureagenesis, oxidation of amino-acids.
41
How is Hydrogen ion homeostasis maintained by buffers?
Buffering – a buffer solution resists changes in pH when acid or base is added to it.
Most important mechanism for regulating pH is through the buffers dissolved in blood – mainly bicarbonate (HCO3-).
H+ + HCO3- <--> H2CO3 <--> CO2 + H2O
[H+ ] = K.[H2CO3 ]/[HCO3-]
[H+ ] = K’.[CO2 ]/[HCO3-]
[H+ ] = K’’.pCO2 /[HCO3-]
so... [H+ ] = pCO2 /[HCO3-]
Another important buffer is haemoglobin (the chloride shift). The Hb group can either hold an O2 or a H+, so when high pCO2, Hb drops O2 (helps it get released into tissues) and picks up H+, affecting the equilibrium of the equation above. The HCO3- that corresponded to the H+ is switched for a Cl- in the plasma to balance changes.
There are other buffers like phosphate and proteins.
There is also the exchange of intracellular K+ for H+ –> intracellular shift of H ions and extracellular shift of K.
42
How is acid-base homeostasis maintained in the lungs?
H+ is excreted rapidly by increasing the amount of CO2 that we exhale. This shifts the below equation to the right as CO2 is removed:
H+ + HCO3- <--> H2CO3 <--> CO2 + H2O
43
How is acid-base homeostasis maintained in the kidneys?
H+ is excreted slowly in the kidneys (takes 2-3 days). The bicarbonate is regenerated, decreasing [H+]. Below equation is thus shifted.
H+ + HCO3- <--> H2CO3 <--> CO2 + H2O
44
What is acidosis?
Excess H+ ions >45 nmol/L.
Respiratory & metabolic causes. Homeostatic mechanisms will try and ‘compensate’.
45
What is alkalosis?
Reduced H+ ions <38 nmol/L.
Respiratory & metabolic causes. Homeostatic mechanisms will try and ‘compensate’.
46
What is respiratory acidosis?
High pCO2 causes increased [H+].
[HCO3-] can increase which lowers [H+], leading to compensated respiratory acidosis (bicarbonate generation and renal hydrogen excretion).
Caused by CO2 retension from a malfunction in the excretory mechanism or it's control.
Examples:
CNS depression/disease or neurological disease (narcotics, stroke, spinal cord lesions, motor neurone disease)
Defects in respiratory function (mechanical - myasthenia, thoracic trauma, pneumothorax; pulmonary disease - restrictive/extensive fibrosis, obstructive - chronic bronchitis/severe asthma, impaired perfusion - massive pulmonary embolism).
47
What is respiratory alkalosis?
Low pCO2 causes decreased [H+].
[HCO3-] generation can decrease and renal excretion of H= decreases, which would compensate to raise [H+], leading to compensated respiratory alkalosis.
Caused by increased rate of excretion of CO2, stimulation of respiratory centre.
Examples:
Hyperventilation;
Stimuli to respiratory centre (cortical - pain, fever; local - trauma, tumours; drugs/toxins - salicylate, liver failure; hypoxaemia - R to L shunts, pulmonary disease).
48
What is metabolic acidosis?
[H+] increases and pCO2 decreases which initially lowers [H+] but then [H+] increases again.
Compensatory responses include buffering leads to further fall in [HCO3-], increased renal H+ excretion (if renal dysfunction not the cause) and hyperventilation (H+ stimulates chemoreceptors, Kussmaul - deep, sighing, lowers pCO2 which lowers H+, limit to how far pCO2 can fall as we need to breathe).
Often due to kidney disease/failure, acid builds up in the body:
Increased H+ generation,
Decreased H+ excretion,
Decreased buffering capacity.
Examples:
Increased acid formation - ketoacidosis (diabetic), lactic acidosis (hypoxia), poisoning (salicylate, methanol);
Reduced excretion - renal failure, renal tubular acidoses (types 1 and 4);
Loss of bicarbonate buffer - gastrointestinal (diarrhoea, pancreatic fistula), renal (renal tubular acidosis type 2)
49
What is metabolic alkalosis?
[HCO3-] increases which causes low [H+] and as a result pCO2 increases.
Often due to kidney disease/failure, excess loss of H+, alkali administration.
Bicarbonate is filtered by the kidneys so for metabolic alkalosis to persist inappropriate renal reabsorption of filtered bicarbonate must occur. This can be due to extra cellular volume contraction, potassium deficiency, mineralocorticoid excess.
Example:
Saline responsive - gastrointestinal (vomiting, gastric drainage), urinary (diuretics - especially in CCF, nephrotic syndrome);
Saline unresponsive - ass’d with hypertension (primary hyperaldosteronism, Cushing’s), not ass’d with hypertension (severe K+ depletion, Bartter’s syndrome).
50
What is the biochemistry of types of respiratory acidosis?
Acute respiratory acidosis:
pCO2 increased, high H+;
Bicarbonate normal or rising
Chronic respiratory acidosis:
pCO2 high, high normal H+;
Compensatory rise in bicarbonate
Acute on chronic respiratory acidosis:
pCO2 high, high H+, high bicarbonate
51
What are the effects of respiratory acidosis?
Of underlying disorder;
Of hypoxia - SOB, drowsy, cyanosis;
Of hypercapnia - Neurological (anxiety, coma, headache, extensor plantars, myoclonus); Cardiovasular (systemic vasodilatation)
52
What are the effects of respiratory alkalosis?
Of underlying disorder;
Of acute hypocapnia - cerebral vasoconstriction (lightheadedness, confusion, syncope, fits), fall in ionized calcium – preioral, peripheral paraesthesia);
Of cardiovascular - increased heart rate, chest tightness, angina.
53
What is the biochemistry of types of respiratory alkalosis?
Acute:
Decrease pCO2, decrease H+, small decrease in bicarbarbonate
Chronic:
Renal compensation results in only marginally low H+, further fall in bicarb (no lower than 12 mmol/l)
54
What is the biochemistry of metabolic acidosis?
Increase H+, decrease HCO3-;
Hyperventilation causes decreased pCO2;
Increased extracellular K+;
Anion gap normal in bicarbonate loss but raised in increased acid production.
55
What are the effects of metabolic acidosis?
Cardiovascular: negative inotropic effect (if severe)
Oxygen delivery: right shift of oxyhaemoglobin dissociation curve - facilitates O2 delivery; reduced 2,3-DPG which causes left shift of curve but takes some hours - impairs delivery
Nervous system: impaired consciousness - little correlation with H+
Potassium homeostasis: Redistribution of H+ into cells in exchange for K+, plasma [K+] rise whilst intracellular [K+] and total body [K+] are depleted
Bone: if chronic acidosis -> buffering by bone phosphate, leads to decalcification
56
How is protection against pathogenic bacteria provided?
Colonisation: commensal flora and colonisation resistance, normal swallowing reflex, epiglottis.
Swallowing: neurological and anatomical factors.
Lung anatomy: mucus and Ciliated epithelium, ‘mucociliary escalator’; cough reflex.
Immunity (innate and adaptive): soluble factors (IgA, defensins, collectins, lysozyme), alveolar macrophages, B- and T-cells.
57
What characterises upper respiratory tract illnesses?
Viral illnesses: Rhinoviruses (45-50%), Influenza A virus (25-30%), Coronaviruses (10-15%), Adenoviruses (5-10%), Respiratory Syncytial viruses (5%), Parainfluenza viruses (5%).
Usually transient, complications: sinusitis, pharyngitis, otitismedia, bronchitis, rarely pneumonia.
May lead to bacterial super-infection.
Influenza A virus in particular causes systemic symptoms.
58
What are common respiratory viruses?
Rhinoviruses; common cold, bronchitis, sinusitis.
Coronaviruses; colds but occasionally severe respiratory illnesses.
Adenoviruses; upper respiratory tract infection, pharyngitis, bronchitis occasional pneumonia.
Respiratory Syncytial viruses; bronhiolitis in small children, severe illness in nursing home residents, pneumonia in immunocompromised.
Parainfluenza viruses; croup.
Influenza A virus; Flu.
SARS-CoV-2 (COVID 19).
59
What are some emerging respiratory virus infections?
SARS-CoV-2 (Covid-19):
Severe respiratory illness with respiratory failure. Emerged as cause of major global pandemic 2019. High mortality and major economic impactt.
SARS-CoV: Severe acute respiratory syndrome associated coronavirus. Outbreak spread from China in 2002. Severe respiratory illness with respiratory failure.
Middle East Respiratory Syndrome novel Coronavirus (MERS-nCV): Individual cases spread from Middle East in 2012. Similar to SARS but low person to person spread.
Avian Influenza: Novel forms of Influenza A virus. Occasional human cases with severe illness. South-east Asia. Associated with exposure to poultry. Low person to person spread to date.
60
What is Pharyngitis aetiology?
b-hemolytic streptococci (Streptococcus pyogenes, Lancefield Group A streptococci)[10-30%].
Other streptococci, Fusobacterium necrophorum [10%], Mycoplasma pneumoniae [3-14%] occurs in epidemics, Corynebacterium diphtheria (travel e.g. Russia), Neisseria gonorrhoea and other sexually transmitted infections.
Viral (70-80%); rhinovirus, adenovirus etc.
Glandular fever Epstein Barr virus.
Acute HIV infection.
(ensure full history including sexual history and travel)
61
What is sinusitis?
Usually viral (as per causes URI).
Bacterial sinusitis (distinguish these from theviral cases to avoid inappropriate antimicrobial use): unilateral pain purulent discharge ± fever of >10d or presenting acutely or with complications.
Micro-organisms; Streptococcus pneumoniae (40%), Haemophilus influenzae (30-35%), Other Moraxella catarrhalis, streptococci.
Complications: brain abscess, sinus vein thrombosis, orbital cellulitis.
62
What is acute epiglottitis?
Formerly an illness of children 2-4 years old who presented with fever, dysphagia, drooling and stridor.
Caused by Haemophilus infuenzae type B (Hib) but now rare due to use of Hib vaccine.
Adults can also have the disease: most severe due to Haemophilus influenzae, also from causes of pharyngitis (other bacterial infections of airway).
Additional pathogens inimmunocompromised e.g. AIDS.
63
What is bordatella pertussis?
Gram-negative, aerobic, pathogenic, encapsulated coccobacillus bacterium of the genus Bordetella, and the causative agent of pertussis or whooping cough.
Acellular vaccine may not give life long immunity and vaccination may have reduced boosting from natural infections.
Clinical features:
Incubation 7-10 (5-21d),
Catarrhal phase 1-2 weeks; rhinorrhoea, conjunctivitis, low-grade fever and at end of phase lymphocytosis,
Paroxysmal phase 1-6 weeks coughing spasms, inspiratory ‘whoop’ post-ptussive vomitting, cough>14d,
Convalescent phase.
Adults chronic cough, paroxysms of coughing and 50% post ptussive vomitting but fairly specific for pertussis.
Complications; pneumonia, encephalopathy, subconjunctival haemorrhage.
64
What is croup?
Acute laryngo-treacheobronchitis.
A disease of children, 6 yo, most 3mo-3years).
Mainly due to Parainfluenza viruses, (also RSV, IAV and other respiratory viruses).
65
What is bronchiolitis?
Infections due to Respiratory syncytialvirus (RSV) [80% - rarely other viruses].
Inflammation of bronchioles and mucus production cause airway obstruction.
66
What is bronchitis?
Aetiology: Frequently viral, but may be bacterial including Haemophilus influenzae or Streptococcus pneumoniae, Moraxella catarrhalis, Mycoplasma pneumoniae.
Clinical Features: Cough may be productive or non-productive, SOB and often wheeze, may be fever but not systemic features of infection, wheeze but no signs of focal consolidation.
May cause acute exacerbations of COPD or asthma with increased wheeze.
Investigations: Arterial blood gas/oximetry for those with chronic lung disease-helps determine if need hospitalisation; CXR shows no features of pneumonia, usually normal.
Treatment: Usually none especially if viral, sometimes antimicrobials. Manage exacerbation of COPD/asthma with steroids and increased inhalers.
67
What is bronchiectasis?
Abnormal dilatation of airways and suppurative infection.
Chronic scarring of lung with excessive sputum production (‘bronchorrhoea’).
Aetiology:
Congenital - Cystic fibrosis, ciliary dysfunction, hypogammaglobulinemia;
Post-infectious - TB, suppurative pneumonia, measles, whooping cough;
Other - Foreign body.
Symptoms: Chronic cough, Copius sputum, Recurrent pneumonia, Weight loss.
O/E: Clubbing; Coarse ‘wet’ crackles.
Can be complicated by haemoptysis.
68
What infections commonly cause pneumonia?
Streptococcus pneumoniae (40%): any age but increases at extremes of age, can be severely ill with respiratory failure or sepsis.
Mycoplasma pneumoniae (~10% peaks in epidemic seasons): usually younger adult, milder illness; may have extrapulmonary features - haemolytic anaemia (cold agglutinins) ,Raynauds (cold agglutinins) erythema multiforme (rash, bullous myringitis (blisters on tympanic membrane), encephalitis.
Chlamydophila pneumoniae (~10%): like M. pneumoniae, maybe older age group; more prolonged wheezing.
Legionella pneumophila and other spp. (<5%): Cluster of cases related to water cooling towers, showers (lives in free living amoeba); severe illness, respiratory failure; may be elderly, immunocompromised; extra-pulmonary features (diarrhoea, abnormal liver function tests, hyponatremia, myalgia, raised creatinine kinase, interstitial nephritis, encephailitis, confusion.
Haemophilus influenzae (<5%),
Klebsiella pneumoniae (rare): homeless and in hospital.
Staphylococcus aureus (low % in community): increased after influenza and in hospital especially, low white blood cell count, ventilator-associated.
Chlamydophila psittaci: exposure to sick birds.
Coxiella burnetti: exposure to partuent animals.
Klebsiella pneumoniae: homeless, alcoholic, hospital-associated.
Pseudomonas aeruginosa: chronic lung disease, immunocompromised, ventilator-associated.
Viruses (≥10%)
69
Who is at risk of pneumonia?
Infants and the elderly,
COPD and certain other chronic lung diseases,
Immunocompromised,
Nursing home residents,
Impaired swallow (neurological conditions etc.),
Diabetes,
Congestive heart disease,
Alcoholics and drug users
70
What is most likely to cause pneumonia in the immunocompromised?
Bacterial:
all the common causes but may be atypical presentations;
Pseudomonas aeruginosa.
Fungal:
Pneumocystis pneumonia (PCP);
Moulds e.g. Aspergillus spp.
Viruses:
Cytomegalovirus (CMV);
Adenovirus;
Respiratory syncytial virus (RSV).
71
What is the treatment for pneumonia?
Prompt but appropriate initiation of antimicrobials; ideally establish diagnosis and start treatment ≤4h.
Use narrowest spectrum to stop spread of resistance, MRSA acquisition and Clostridium difficile infection.
Mild severity pneumonia in community:
Oral antimicrobial e.g amoxicillin for short duration.
Severe:
Intravenous often in combinations e.g co-amoxiclav + oralclarithromycin;
Duration 7d mild-moderate, 7-10d severe;
14-21d S. aureus, Gram-negative bacteria, and Legionella sp.
72
What is tuberculosis?
Chronic respiratory tract infection (can also be extrapulmonary), usually due to reactivation of latent infection.
Specific epidemiological groups e.g.: exposed to a case, born in country of high incidence, homeless, alcoholic HIV infection, anti-TNF treatment.
Clinical features: Cough, hemoptysis, short of breath; weight loss, fever, night sweats; swollen lymph nodes or other extrapulmonary features.
Multiple radiological appearances but upper lobe disease with cavities; pleural disease; multiple tiny nodules (‘miliary’); lymphadenopathy in chest.
And failure to resolve with routine antibiotics is suggestive.
Patients require isolation if admitted as may be highly infectious to others.
73
What is the treatment for tuberculosis?
Use Ziehl-Neelsen stain to visualise the bacteria and prolonged culture in special media e.g. Mycobacteria growth indicator tube (MGIT).
Prolonged treatment 6mo or longer.
Treatment with multiple drugst o avoid resistance, but resistance is common e.g. Isoniazid, Rifampicin, Pyrazinamide, Ethambutol.
74
What are some chronic pneumonias (other than TB)?
Bacterial:
Nocardia spp. (immunocompromised),
Burkholderia pseudomallei (SE Asia, N Ausatralia),
Non-tuberculous mycobacteria.
Fungal:
Histoplasma capsulatum and other dimorphic fungi (Americas and other regions),
Moulds e.g. Aspergillus spp. (patients with haematological malignancy).
Parasites:
Echinococcus granulosus (dog tapeworm).
Non-infectious: malignancy, vasculitis, chronic interstitial pneumonia, drugs, eosinophils, organising pneumonias.
75
76
What is mechanical and immunological defence to Parenchymal lung disease?
Mechanical: ciliated epithelium, mucus, cough;
Immunological: IgA & antimicrobials in mucus, resident alveolar macrophages & dendritic cells, innate/adaptive immune responses
77
What are pneumocytes (type 1 and 2)?
Type 1 pneumocytes are alveolar cells that line the alveolar surface, allow gas exchange.
Type 2 pneumocytes are alveolar cells that secrete surfactant to reduce surface tension.
Type 1 pneumocytes are flat and thin. Type 2 pneumocytes are cubic in shape.
78
What is the parenchyma?
The parts of the lungs involved in gas transfer including the alveoli, interstitium, blood vessels, bronchi and bronchioles.
79
What are the categories of pneumonia?
Community acquired
Hospital acquired
Health care associated
Aspiration associated
Immunocompromised host
Necrotising/abscess formation
80
What pathogens are likely to cause community acquired pneumonia?
Most likely:
Streptococcal pneumoniae,
Haemophilus influenzae,
Less likely:
Moraxella catarrhalis,
Staphylococcus aureus,
Klebsiella pneumoniae/Pseudomonas aeurginosa,
Mycoplasma pneumoniae
81
What pathogens are likely to cause hospital acquired/health care associated pneumonia?
Gram-negative rods, Enterobacteriaceae, Pseudomonas;
Staphylococcus aureus (usually methicillin-resistant)
82
What pathogens are likely to cause aspiration pneumonia?
Anaerobic oral flora mixed with aerobic bacteria.
83
What pathogens are likely to cause pneumonia in the immunocompromised host?
Cytomegalovirus,
Pneumocystis jiroveci (PCP),
Mycobacterium avium-intracellulare,
Invasive aspergillosis,
Invasive candidiasis,
“Usual” bacterial, viral, and fungal organisms.
84
What pathogens are likely to cause necrotising/abscess formation pneumonia?
Anaerobes, S. aureus, Klebsiella, S. pyogenes
85
What is the cellular response to infection?
Neutrophils:
Chemotaxis,
Degranulation,
Reactive oxygen species,
Extracellular traps,
Phagocytosis
Macrophages:
Cytokine & chemokines,
Phagocytosis (bacteria & dead cells),
Antimicrobial peptides,
Resolution (also involves Tcells, dendritic cells & epithelial cells)
86
What is the clinical presentation of lung infection?
Cough, sputum, pyrexia, pleuritic chest pain, haemoptysis, dyspnoea, hypoxia.
87
What are the appearances of broncho- and lobar- pneumonia?
Bronchopneumonia:
Most common pattern,
Patchy consolidated areas of acute suppurative inflammation,
Often elderly with risk factors (cancer, heart failure, renal failure, stroke, COPD)
Lobar pneumonia:
Rust coloured sputum,
S. pneumoniae,
Consolidation of a large portion of a lobe or of an entire lobe
88
What are general and local risk factors for pneumonia?
General factors:
Chronic diseases,
Immunologic deficiency,
Immunosuppressive agents,
Leukopaenia
Local factors:
Loss or suppression of the cough reflex (drugs),
Injury to the mucociliary apparatus (viruses, gases),
Accumulation of secretions (CF, obstruction - tumour),
Impaired alveolar macrophages function (alcohol, tobacco),
Pulmonary congestion and oedema
89
What are local and systematic complications of pneumonia?
Local:
Abscess formation,
Parapneumonic effusion,
Empyema
Systemic:
Sepsis,
ARDS,
Multi-organ failure (liver/renal/cardiac…)
90
What is acute respiratory distress syndrome?
Incidence 10-14/100,000/yr;
Mortality rate ~40%
Clinical diagnosis:
Hypoxia (PaO2/FiO2 ≤ 300mmHg),
Non-cardiogenic pulmonary oedema
Causes:
Direct – pneumonia, aspiration, hyperoxia, ventilation
Indirect – sepsis, trauma, pancreatitis, acute hepatic failure
91
What is bronchiectasis (chronic inflammation)?
The permanent dilatation of one or more large bronchi.
Typically affects the 2nd to 8th order of segmental bronchi - largest central airways more robust.
92
What is cystic fibrosis?
Multi-system disorder affecting lungs, GI tract…
∆F508 (autosomal recessive) most common (Chr 7 q31.2)
Loss of function/reduced function in CFTR
Altered ion transportation
Viscous mucoid secretions due to H2O resorption
93
What are causes of chronic Parenchymal lung inflammation?
Lung abscess - bacteria/fungi;
Fungal infection - Aspergillus, Mucormycoses;
Vasculitis;
Connective tissue disease – Rheumatoid arthritis
94
What are predisposing factors to TB?
Alcoholism, diabetes mellitus, HIV/AIDS, some ethnic groups
95
What is TB?
Infection vs disease; host-organism relationship, immune response very important (11% of TB cases attributable to HIV in 2000).
Treatment:
Socio-economic conditions; drugs - triple antibiotic therapy; prevention (BCG vaccine…)
96
What is primary tuberculosis?
3-4 weeks:
M. TB multiplies within alveolar macrophages (naive, unable to kill),
Bacterium resides in phagosomes & carried to regional lymph nodes, from there to circulation;
3-8 weeks:
Onset of cellular immunity & delayed
hypersensitivity,
Activated lymphocytes further activate macrophages to kill,
Primary infection arrested in most immunocompetent people,
Few bacilli may survive dormant
97
What is progressive primary tuberculosis?
Infection not arrested - minority (infants, children, immunocompromised most likely)
Tuberculous bronchopneumonia:
Infection spreads via bronchi, results in diffuse bronchopneumonia, well developed granulomas do not form
Miliary Tuberculosis:
Infection spreads via blood-stream, organisms scanty, multiple organs (lungs, liver, spleen, kidneys, meninges, brain)
98
What is secondary tuberculosis?
Also termed ‘Post-primary’ TB.
Reactivation of old, often subclinical infection,
Occurs in 5-10% of cases of primary infection,
More damage due to hypersensitivity:
Apical region of lung,
Tubercules develop locally, enlarge and merge,
Erode into bronchus and cavities develop,
May progress to tuberculous bronchopneumonia.
99
What are causes of granulomatous pulmonary inflammation?
TB,
Other infection – fungi,
Sarcoidosis,
Rheumatoid arthritis,
Berrylosis,
Hypersensitivity pneumonitis,
Aspiration pneumonia,
Langerhans Cell Histiocytosis
100
What do fibrosing diseases of the lung present as?
Slowly worsening shortness of breath, cough and ankle oedema.
CT scan – honeycomb and ground glass changes in both lower lobes.
Restrictive defect on pulmonary function tests.
101
What are characteristics of Fibrosing diseases of the lung?
Restrictive chronic lung disease;
Dyspnoea, (cough), tachypnoea, crepitations, cyanosis (late stage).
Pulmonary function tests show reduced transfer factor and total lung capacity;
Ground glass changes in lower zones on x-ray.
102
What is idiopathic pulmonary fibrosis?
Unclear pathogenesis.
Under the microscope:
Usual interstitial pneumonia,
Morphology - Subpleural accentuation, Spatial & temporal heterogeneity, Fibroblastic foci, Mixed inflammatory infiltrate, Excess alveolar macrophages.
103
What does asbestos cause?
Occupational lung disease:
Exposure in shipyards, building trade
Several diseases:
Pleural plaques (benign),
Asbestosis (progressive fibrosis),
Mesothelioma,
Adenocarcinoma
Issues surrounding compensation for patient and families.
Other occupational factors: silica, coal dust, berrylium
104
What is hypersensitivity pneumonitis?
Type III hypersensitivity: Ab/Ag complex within the lung
Various causative agents:
Farmer’s lung,
Pigeon fancier’s lung,
Mushroom picker’s lung,
Hot tub lung (!)
Most resolve when agent of exposure removed but can be chronic.
105
What factors can contribute to increased risk of respiratory infection?
The same infectious agent can produce markedly different effects in different people.
Defences:
Cough reflex
Cilia
Mucus
Antibody deficiency e.g. IgA
Immunosuppression - disease, drugs
Macrophage dysfunction
Pulmonary oedema
106
What is acute bronchitis?
Inflammation of bronchi; often viral, may be bacterial (e.g. H influenzae); may also involve larynx and trachea - laryngotracheobronchitis. Acute exacerbations of ‘chronic bronchitis’ are common.
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What is bronchiolitis?
Inflammation of bronchioles.A feature of chronic bronchitis.
Primary bronchiolitis:
Usually in children,
Caused by respiratory syncytial virus (RSV),
Tachypnoea and dyspnoea.
Rare types:
Follicular bronchiolitis,
Bronchiolitis obliterans.
108
What is a Localised Airway Obstruction?
Airway obstruction:
Lesion outside the wall (e.g. large lymph node),
Lesion in the wall (e.g. tumour),
Lesion in the lumen (e.g. foreign body).
Causes distal collapse or over-inflation. May be distal lipid or infective pneumonia. Normal pulmonary function tests.
109
What is a Diffuse Airway Obstruction?
Reversible and intermittent OR Irreversible and persistent (or a mix).
Centred on bronchi and bronchioles. Diffuse disease as many airways involved. Pulmonary function tests ‘obstructive’: Reduced vital capacity (VC), Reduced FEV1 / FVC ratio, Reduced peak expiratory flow rate.
Several clinico-pathological entities: Chronic bronchitis, Emphysema, Asthma, (Bronchiectasis), COPD (spectrum of co-existence of chronic bronchitis and emphysema).
110
What is chronic bronchitis?
Cough and sputum for 3 months in 2 consecutive years.
Aetiology - pollution, smoking.
Clinical:
Middle-aged heavy smokers,
Recurrent low-grade bronchial infections (exacerbations),
H. influenzae, S. pneumoniae, viruses,
Airway obstruction may be partially reversible.
Progression of disease:
Hypercapnia,
Hypoxia,
Pulmonary hypertension,
‘Cor pulmonale’ - right ventricular failure.
Pathology:
Respiratory bronchiolitis (<2mm diameter),
Can lead to centrilobular emphysema,
Mucus hypersecretion (mucous gland hypertrophy),
Chronic bronchial inflammation (squamous metaplasia, increased risk of malignancy).
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What is emphysema?
Irreversible dilatation of acinar spaces withdestruction of walls.
Traditional definition confined to alveoli but often extended to include respiratory bronchioles.
Associated with loss of surface area for gas exchange.
Clinical features:
Hyperventilation,
Normal pO2, pCO2,
Weight loss,
Right ventricular failure,
Often co-existing chronic bronchitis, in which case clinical features are mixed.
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What are the different types of emphysema?
Centrilobular Emphysema: Most common (95%); Strongly associated with smoking; Seen in some with pneumoconiosis, particularly coal-workers; Most commonly in upper lobes; Respiratory bronchiolitis often present.
Panlobular Emphysema: Usually lower lobes; Lungs overdistended; Associated with alpha-1-antitrypsin deficiency; Markedly accelerated in smokers with this disorder.
Paraseptal Emphysema: Distension adjacent to pleural surfaces; May be associated with scarring.
Irregular Emphysema: Associated with scarring; Overlap with paraseptal emphysema.
Bullous Emphysema: distended areas >10mm.
Interstitial Emphysema.
113
What lung abnormality defines the emphysema component of COPD?
Acinar collapse,
Acinar dilatation,
Acinar inflammation,
Acinar wall destruction,
Bronchial dilatation
114
What is COPD?
Incorporates a combination of chronic bronchitis and emphysema, which affect the airways and the lung parenchyma respectively.
Leads to symptoms related to airways obstruction (reversible and/or fixed) and loss of surface area for gas exchange.
Airway involvement also leads to a productive cough as a result of increased mucus production.
Relative contribution varies between individuals.
Symptoms:
Destruction of alveolar walls leads to loss of surface area for gas exchange,
Increased respiratory drive compensates for the drop in pO2,
pCO2 may be low due to the high respiratory rate,
In some cases, respiratory drive may fall, with tolerance of a low pO2 and elevation of pCO2,
Pulmonary vasoconstriction (due to hypoxia) and destruction of pulmonary vasculature lead to pulmonary hypertension.
115
How is COPD diagnosed?
Diagnosis based on FEV1/FVC < 0.7 (airflow limitation).
Severity assessed by percent predicted post-bronchodilator FEV1. GOLD criteria (global initiative for chronic obstructivelung disease):
FEV1 ≥ 80 – mild
FEV1 50–79 – moderate
FEV1 30–49 – severe
FEV1 < 30 – very severe
116
What is the eventual consequence ofchronic pulmonary hypertension?
Acute bronchitis,
Left ventricular heart failure,
Pneumonia,
Pulmonary embolism,
Right ventricular heart failure
117
What are the consequences of Right Ventricular Failure?
Ankle swelling,
Hepatic congestion - Pain, Abnormal liver function tests, ‘Nutmeg’ liver.
118
What is asthma?
‘Reversible wheezy dyspnoea’.
Increased irritability of the bronchial tree with paroxysmal airway narrowing.
Five aetiological categories: Atopic, Non-atopic, Aspirin-induced, Occupational, Allergic bronchopulmonary aspergillosis (ABPA).
119
What is atopic asthma?
Associated with allergy; triggered by a variety of factors - dust, pollen, house dust mite…
Often associated with eczema and hay fever.
Bronchoconstriction mediated by a type I hypersensitivity reaction.
Hypersensitivity reaction leads to:
Bronchial obstruction with distal overinflation or collapse,
Mucus plugging of bronchi,
Bronchial inflammation,
Mucous gland hypertrophy,
Bronchial wall smooth muscle hypertrophy,
Thickening of bronchial basement membranes.
120
What is non-atopic asthma?
Associated with recurrent infections. Not immunologically mediated. Skin testing negative.
121
What is aspirin-induced asthma?
Associated with recurrent rhinitis, nasal polyps and urticaria.
Mechanism of asthma unclear (maybe Prostaglandins, Leukotrienes).
122
What is occupational asthma?
Hypersensitivity to an inhaled antigen. May be non-specific in those with hyper-reactive airways. May be a specific allergic response.
123
What is Allergic Bronchopulmonary Aspergillosis (asthma)?
Specific allergic response to the spores of Aspergillus fumigatus.
Mixed type I and type III hypersensitivity reaction; Mucus plugs common; Associated with bronchiectasis.
Not to be confused with an aspergilloma, which is a fungal ball, usually colonising a pre-existing cavity in the lung (often tuberculous).
124
What is the main abnormality in asthma?
Bronchoconstriction,
Hypersensitivity reaction,
Mucous gland hypertrophy,
Mucus plugging,
Muscle hypertrophy.
125
What are Factors that Contribute to Airways Obstruction in Asthma and Their Relationship to Therapy?
Mucus plugging: Physiotherapy, Bronchodilators useful in conjunction with physiotherapy.
Bronchoconstriction: Bronchodilators (particularly beta2agonists like salbutamol).
Bronchial oedema and inflammatory cell infiltration: Anti-inflammatory agents (e.g. inhaled/oral steroids), leukotriene receptor antagonists.
Smooth muscle hypertrophy and basement membrane thickening: Irreversible once developed (prevention of inflammation using inhaled steroids important).
126
What is bronchiectasis?
Permanent dilatation of bronchi and bronchioles. Bronchial dilatation, acute & chronic inflammation, fibrosis.
Due to a combination of obstruction and inflammation (usually infection); may be localised or diffuse, depending on cause.
Historically seen in patients with pulmonary tuberculosis involving hilar lymph nodes; classically associated with childhood infections, particularly measles and whooping cough.
Diffuse bronchiectasis seen in patients with cystic fibrosis.
Clinical features:
Chronic cough productive of copious sputum,
Finger clubbing.
Complications:
Spread of infection - Pneumonia, Empyema, Septicaemia, Meningitis, Metastatic abscesses e.g. brain),
Amyloidosis,
Respiratory failure
127
What happens during airway narrowing?
Narrowing of airways caused by: smooth muscle constriction, mucus, inflammation, fluid, oedema.
This all causes increases resistance, leading to reduced gas airflow and reduction of inflation of alveoli.
Air flows down pressure gradient:
Airflow = (upstream pressure - downstream pressure) / resistance
Small changes in radius change resistance and have massive effect.
Goblet cells produce mucus and cilia beat to escalate back up the airway to clean.
Too much and too thick mucus means it gets stuck, limits diameter. Bacteria can also get trapped which causes infection - pneumonia.
Airways are dynamic - bronchoconstriction happens quickly in response to agonists. This also means quick to respond to medications though.
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What is the effect of the autonomic and NANC (nonadrenergic, noncholinergic) Nervous Systems in the airway smooth muscle?
Muscarinic receptors (M3) cause constriction (bronchoconstriction) when acetyl choline binds - response to parasympathetic NS (via vagus nerve).
Beta-2-adrenergic receptors cause dilation (bronchodilation) when adrenaline binds in response to sympathetic NS.
(NANC) nerves cause bronchodilation of airway smooth muscle in response to VIP and NO, and bronchoconstriction in response to substance P and neurokinins.
Beta-2 agonists cause dilatation (sympathetic NS).
Muscarinic antagonists act on muscogenic receptors (parasympathetic/vagus) to stop constriction.
Nitric oxide used diagnostically - high levels on exhale (if stimulated), suggests asthma (if non-smoker).
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What is asthma?
Chronic airway inflammatory disorder characterized by airway hyperreactivity to a variety of non specific stimuli leading to variable airway obstruction (normally reversible but may become irreversible if chronic/untreated).
Inflammation of the small and large airways - Airway obstruction occurs - Inflammatory cell infiltration, Mucus hypersecretion, Smooth muscle contraction.
Asthma characterized by reversible airways obstruction and an early and late phase response to stimuli.
Clinical Diagnosis: Symptoms (>1 of wheeze, breathlessness, chest tightness, cough); Variable airflow obstruction; Clinical Assessment Supported by Objective tests that seek to demonstrate airflow obstruction (peak flow/spirometry) or the presence of airway inflammation (FeNO).
130
What is COPD?
Persistent respiratory symptoms and airflow limitation.
Fixed airway obstruction; minimal or no reversibility with bronchodilators; minimal variability in day to day symptoms; slowly progressive and irreversible deterioration in lung function.
Increased mucous production alongside destruction of alveoli and connective tissue leading to collapse of conducting airways.
131
What is peak flow?
Peak expiratory flow rate (PEFR); measures maximum speed of expiration; crude measurement of conducting airway flow; can aid in Asthma diagnosis/management; excellent bedside and patient based tool.
Asthmatic people will often see a ‘morning dip’.
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How do you categorise acute asthma in adults?
Moderate Acute Asthma:
Increasing Sx,
PEF >50-75% best or predicted,
No features of acute severe asthma.
Acute Severe Asthma:
PEF 33-50% best or predicted,
RR >25/min,
HR >110/min,
inability to complete sentences in 1 breath.
Life threatening asthma:
PEF <33% predicted,
SpO2 <92%,
PaO2 <8kPa,
‘normal’ paCO2 (4.6-6 kPa),
altered conscious level, exhaustion, arrhythmia, hypotension, silent chest, poor respiratory effort.
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How is spirometry used?
FEV1/FVC ratio of >0.7 is considered normal.
Ratio of <0.7 suggests obstructive airways pathology.
Mild obstruction has biggest impact on FEV1; severe obstruction can also lose FVC (due to gas trapping).
Asthma is reversible following a bronchodilator, used as a diagnostic test; COPD is not as reversible.
If FEV1 is less than 1L then they likely wont do well on ventilator - good to know for escalation and prognosis.
134
What’s the difference between obstructive and restrictive lung disorders?
OBSTRUCTIVE DISORDER: A disorder in which the radius of an airway is narrowed, thusreducing airflow in and out of the lungs.
RESTRICTIVE DISORDER: A disorder in which prevents normal expansion of the lungs.
135
What causes lung restriction to occur?
Extra-pulmonary disease - visceral pleura, pleural space, chest wall (parietal pleura, bones, muscles, nerves).
Intra-pulmonary disease - alveoli and surrounding lung tissue (parenchyma).
136
What types of conditions cause extra-pulmonary restriction?
Integrity of nerves to respiratory muscles (like high cervical dislocation).
Impaired neuromuscular junctions (like myasthenia gravis).
Pleural thickening (like asbestos exposure).
Impaired muscles (like muscular dystrophy).
Skeletal abnormalities (like scoliosis).
137
What conditions can cause intra-pulmonary restriction?
Diseases causing increased fibrous tissue in the lungs:
Silicosis - stonemason
Asbestos
Drug-induced lung fibrosis
Coal-workers’ pneumoconiosis
Rheumatoid-lung
Bird-fanciers’ lung
Idiopathic pulmonary fibrosis
138
What are the mechanics of lung inflation?
The lung has a tendency to recoil inwards (lung elastic recoil pressure). The chest wall has a tendency to recoil outwards (chest elastic recoil pressure).
The difference between the lung and chest wall elastic recoil pressure is called the transpulmonary pressure.
To inflate the lungs, we could apply an inflation pressure, or, increase the volume of the thoracic cage thereby lowering pleural pressure and alveolar pressure and creating a pressure gradient.
139
What is compliance?
The measure of distensibility (stretchability) of a tissue.
A lung with low compliance means a greater inflation pressure is required to inflate the lung.
A lung with low compliance generates more elastic recoil (deflation is easy).
A lung with high compliance means a smaller inflation pressure is required to inflate the lung.
A lung with high compliance generate less elastic recoil (deflation is hard).
140
What is the effect of decreased compliance on inflation?
With the same inflation pressure, the lung volume will not be able to increase as much.
More fibrous tissue means it’s more rigid so needs high pressure to inflate. Has increased elastic recoil so deflates easily.
141
What is the effect of increased compliance on inflation?
With the same inflation pressure, lung volume will be bigger.
Has decreased elastic tissue so more floppy, so inflates at a lower pressure. It has decreased elastic recoil so difficult to deflate.
142
What is the effect of alveolar lining fluid?
Moisture causes surface tension which influences the pressure inside a sphere.
Inward force is generated but fluid layer surface tension (sT).
Laplace’s law for a sphere:
Pressure (force) exerted by sT = 2sT/radius
The larger the radius of the alveoli, the lower the additional pressure exerted by surface tension. So small alveolar have a high additional inward pressure exerted by sT.
This creates instability of adjacent alveoli since the smaller, under-inflated alveolus has high pressure and larger, well-inflated alveolus has lower pressure. Air moves from high to low pressure so smaller alveolus empties into larger alveolus.
143
What is surfactant?
Produced by alveolar Type II cells, composed of lipids (90% - mainly phospholipids) and proteins (10%). This reduces surface tension.
Prevents collapse and keeps alveoli stable.
Hydrophilic end (glycerol, phosphate, choline) stays in the liquid; hydrophobic end (2x fatty acids) stays in the gas.
Surfactant molecules act to reduce surface tension but only when theyare close together.
During inspiration when alveoli are well-expanded, surfactant has little effect on surface tension since it’s spread evenly over alveolar space, meaning molecules are spread out.
During expiration, when alveoli are deflated, surfactant molecules are tightly packed, with some also extruded from the surface. the surfactant this significantly reduces surface tension and thus lowers pressure.
144
What is respiratory distress syndrome of the newborn caused by?
Lack of surfactant.
It is first produced at 30 weeks (210 days).
Without leads to alveolar collapse and instability, causing hypoxia and increased work breathing.
Primary surfactant deficiency is very rare in adult disease, but impaired surfactant biology probably contributes to the pathogenesis of common respiratory disorders like Adult respiratory distress syndrome (ARDS), Pneumonia, Idiopathic pulmonary fibrosis, Lung transplant…
145
What are pattern of abnormal lung function tests (spirometry and lung volume) in obstructive and restrictive diseases?
Obstructive: FEV1 low, FVC normal, FEV1/FVC low, TLC high, VC low, RV high, RV/TLC high
Restrictive: FEV1 low, FVC low, FEV1/FVC normal or high, TLC low, VC low, RV normal or low, RV/TLC normal or high
146
How are extra- and intra- pulmonary restrictive diseases distinguished?
Spirometry and lung volumes are the same for both. (FEV1 low, FVC low, FEV1/FVC normal or high, TLC low, VC low, RV normal or low, RV/TLC normal or high)
We use gas transfer measurement. Gas transfer is measure of diffusing capacity of the lung, requires measurements of gas exchange and alveolar volume.
147
How is Gas Transfer Measurement measured?
Gas transfer is measure of diffusing capacity of the lung, requires measurements of gas exchange and alveolar volume.
Gas exchange: use carbon monoxide [CO], readily taken up by haemoglobin with very high affinity, not produced by the body, non-toxic, easy to measure.
Alveolar volume: use helium [He], not taken up by haemoglobin, not produced by the body, non-toxic, easy to measure.
We use the single breath method. Inspired test gas contains 0.3% CO, 10% He and air. Breathhold at TLC for approx 10 secs, washout and take alveolar sample.
We use this to calculate V(A) = alveolar volume, number of contributing lung units; TLCO (mmol/min/kPa) = total CO exchange capacity; KCO = efficiency of gas transfer per unit of lung.
148
What will extra- and intra- pulmonary restrictive diseases show on gas transfer measurement?
Extra-pulmonary: TLCO low (lungs are smaller); KCO normal or high (alveoli are normal and tightly packed with blood vessels).
Intra-pulmonary: TLCO low (lungs are smaller); KCO low (alveoli are abnormal).
149
What are particulates?
The term ‘particulates’ relates to the exposure to a dry aerosol composed of separate particles which are themselves scientifically defined as very small pieces of solid matter.
Particulates are everywhere and come from a variety of sources, both naturally occurring (like dusts) and man-made (like Diesel exhaust).
We are constantly exposed and our body has evolved numerous mechanisms to deal with particles.
The risk of disease resulting from particles is largely composed of the inherent toxicity of aparticle (hazard) and the level of exposure.
risk = hazard x exposure
150
What are nanoparticles?
Particulates that have one or more dimensions less than 100nm.
Nanoparticles cause more inflammation than the same mass of fine respirable particles composed of the same material.
151
What is silicosis?
Lung disease caused by inhaling large amounts of crystalline silica dust. It is formed by combining 90% ground quartz with 8-10% resins, polymers, and pigments. As with any surface, it requires cutting and sanding during manufacture and instillation, creating exposure potential and disease risk.
Historically killed a lot of stonemasons.
152
How does particle exposure relate to lung deposition?
Penetration of the lungs (and deposition) is based upon aerodynamic diameter.
Inhalable fraction – the mass fraction of total airborne particles which is inhaled through the nose and mouth.
Extrathoracic fraction – the mass fraction of inhaled particles failing to penetrate beyond the larynx.
Thoracic fraction – the mass fraction of inhaled particles penetrating beyond the larynx.
Respirable fraction – the mass fraction of inhaled particles penetrating to the unciliated airways. Respirable = <4.25μm
153
How is lung deposition related to aerodynamic diameter?
Penetration and deposition of particles is based upon the aerodynamic diameter.
The aerodynamic diameter (Dae) of a particle is defined as the diameter of a unit density (1g/cm3) sphere with the same settling speed as the particle of interest.
In simple terms this means that if we have an irregular shave with a settling speed of X then its aerodynamicdiameter is the diameter of a perfect sphere with adensity of 1g/cm3 which falls at the exact same rate as the irregular shaped particle in question.
Inhalable fraction – the mass fraction of total airborne particles which is inhaled through the nose and mouth.
Extrathoracic fraction – the mass fraction of inhaled particles failing to penetrate beyond the larynx.
Thoracic fraction – the mass fraction of inhaled particles penetrating beyond the larynx.
Respirable fraction – the mass fraction of inhaled particles penetrating to the unciliated airways. Respirable = <4.25μm
154
How is particle exposure dealt with?
Some is deposited in the lung and accumulates there.
Some particles are translocated (e.g. to the spleen).
Some particle clearance happens as it get trapped in mucus and brushed up by cilia.
Some particle clearance because macrophage engulfs it, so carbon/fibre glass(…) deposits held enclosed in the macrophage (fibres less than 10μm).
155
What are fibres (particle exposure)?
Fibres are defined as having a length greater than 5μm, a diameter less than 3μm and a length to width ratio of greater than 3:1.
Naturally Occurring: Asbestos, Pele’s Hair, Plant Fibres (Cotton…)
Man-Made: Insulation wools, Refractory Ceramic Fibres, Silicon Carbide, Carbon Nanotubes
A respirable particle has an aerodynamic diameter (Dae) of less than 4.25μm. A fibres aerodynamic diameter is based on its physical diameter, not its length.
Fibres of greater than 20μm can commonly be found in the lung. The aerodynamic diameter of platelets such as graphene is based on thickness.
156
What diseases do fibres cause?
Bronchogenic carcinoma,
Asbestos honeycomb lung,
Pleural mesothelioma,
Pleural plaque,
Peritoneal mesothelioma
157
What is the fibre pathogenicity paradigm?
Fibrous shape represents an attribute conveying enhanced toxicity to a particle due to the physical hindrance of normal clearance from the thoracic region and interaction with cells.
This is because it’s:
Thin - small aerodynamic diameter enables deposition beyond the ciliated airways,
Bio-resistant - retains it’s long term shape over long-term residence in the lung,
Long (longer than 15-20μm) - cannot be completely enclosed by a macrophage producing frustrated phagocytosis.
158
What is the frustration of normal clearance for fibres?
They’re too long to be completely enclosed by a macrophage, producing frustrated phagocytosis (longer than 15-20μm).
The fibre damages the cell, causing inflammation and injury so cell contents are released from cell.
Failure of normal movement in the macrophage results in an inability to clear the long fibres out of the lungs.
159
How does the body deal with fibre exposure?
Fibre exposure causes deposition in the lungs.
Short fibres can be effectively cleared by phagocytosis and macrophage clearance.
Non-biopersistent long fibres go through dissolution and are then broken down and treated as short fibres or completely dissolved.
Biopersistant long fibres go through incomplete phagocytosis, cell activation, and failed clearance. This leads to inflammation, fibrosis and cancer.
160
How does the mesothelium affect the dose of fibres (particles) in the lung?
Mesothelium is the lining of the pleural membranes (visceral and parietal).
Some fibres cross visceral pleural (attached to long tissue) into the pleural space. From here, lymphatic drainage can take it out of the pleural space into the lymphatic channel (between the chest wall and the parietal pleural).
A fraction of all deposited particles transit through the pleural space.
It is only particles that cannot negotiate the stomatal openings where lymph leaves the pleura space on the parietal pleura that remain and they will cause inflammation.
161
What is the effect of dimension of the fibres causing toxicity in the lung?
The toxicity of fibres is length dependent.
The fibres can be categorised into short (which can be cleared my phagocytosis/macrophages) and long which, if also biopersistent, are harmful.
162
What is the effect of durability of long fibres causing toxicity in the lung?
Fibre biopersistence (the ability to persist in the biological environment) is a key attribute of a pathogenic fibre.
Made up of a combination of processes:
Physiological - clearance (mucociliary, macrophage mediated), translocation; and
Physiochemical - biodurability - dissolution, leaching, breaking within extracllular (lung lining fluid…) or intracellular (macrophage phagolysosome…) environment.
They are retained according to their half lives:
Short [T1/2 < 40days] - non-pathogenic (limited inflammatory response), or,
Long [Tq/2 > 40days] - pathogenic (chronic inflammation, fibrosis, cancer).
163
What are the dangers of asbestos?
High levels of exposure to asbestos can cause fibrotic lung disease.
Asbestos deposited in the lung can move through to the pleura and present a dose to the parietal pleura.
A component(s) of asbestos can drive carcinogenic changes resulting in the formation of mesothelioma over time.
Asbestos is a biologically effective dose (BED) for mesothelioma.
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What are the dangers of carbon nanotubules?
Exposure to carbon nanotubes can cause lung fibrosis in experimental models.
Carbon nanotubes deposited in the lung can move through to the pleura in experimental models.
Carbon nanotubes, above a threshold length, can drive local inflammation, fibrosis and granuloma formation.
Carbon nanotubes could be a BED (biologically effective dose) for mesothelioma or other forms of fibre-associated cancer.
