lecture 19: Airflow limitation: from bench to bedside

Question 1

What is asthma?

Answer 1

• a chronic inflammatory disorder of the airways
• often associated with atopy → group of allergic type disorders e.g. hayfever, eczema
• frequently involves chronic inflammation, associated with airway hyperresponsiveness
• symptoms: recurrent episodes of wheezing, breathlessness, chest tightness, and coughing
• widespread, variable, usually reversible airflow limitation

Question 2

What is the pathophysiology of asthma?

Answer 2

• most often occurs in response to an allergen, though not always
• the inciting event will stimulate one of two different effector cell types
• most commonly the mast cell
• resident leukocytes within the lung, in particular macrophages
• mucus production
• goblet cell hyperplasia → mucus hypersecretion → thickening of airway wall and sputum production
• angiogenesis and increased tissue within the submucosal layer → smooth muscle and inflammatory cell infiltrate

Question 3

What remodelling occurs in the asthamatic?

Answer 3

• goblet cell metaplasia
• subepithelial collagen thickening
• infiltration of inflammatory cells and increased mucosal vascularity
• increased smooth muscle volume
  
  • rarely see smooth muscle in a normal airway biopsy

Question 4

What are the clinical consequences of asthma?

Answer 4

• acute inflammation
  
  • symptoms → bronchoconstriction
  • symptoms
• chronic inflammation
  
  • exacerbations, non-specific hyperreactivity → exacerbations
  • different clinical phenotype
  • much more persistent symptoms
  • much higher degrees of airway hyperresponsiveness
  • can have chronic cough because of those persistent issues
• airway remodelling → persistent airflow obstruction → exacerbations
  
  • if chronic inflammation is not addressed the changes can become fixed
  • fixed airway obstruction
  • not typically how we envision asthma to be
  • occurs with poorly controlled disease
  • epithelial collagen thickening, smooth muscle hypertrophy → fixed, persistent airway obstruction so that even when they are well they have ventilatory limitation

Question 5

What is impact of airway wall remodelling on function?

Answer 5

• thin-walled airway and therefore large luminal diameter → significant bronchoconstriction of the smooth muscle producing only a modest amount of increase in airway resistance
• Poiseuille’s law → resistance of a gas travelling through a tube → the narrower the luminal diameter the markedly higher the airway resistance will be
• therefore people with chronic airflow obstruction have a significant limitation even in between episodes
• not only significantly reduced luminal diameter through which breathing can occur, but also much higher airway resistance → much higher work of breathing

Question 6

To what does airway narrowing lead?

Answer 6

• airflow limitation (obstruction)
• FEV1 = amount of air they can push out within 1 second
• FVC = entirety of large breath
• FEV1 is what is most affected in patients with obstructive lung disease, moreso than FVC
• particularly with mild to moderate airway obstruction, patients will have a relatively conserved FVC
• much slower rate of expiration of their lung capacity
• narrower airway therefore takes longer for air to be exhaled
• FEV1 is the parameter by which degree of airway obstruction is measured

Question 7

Why do patients feel breathless with obstructed airways?

Answer 7

• there is a change in the “work of breathing”
  
  • change in the “load” (resistive, elastic)
• breathlessness → a recognition of an inappropriate degree of respiratory work for body workload
• often a very significant limitation for patients

Question 8

What is the burden of asthma?

Answer 8

• asthma is one of the most common chronic diseases worldwide – estimated 300 million affected individuals
• prevalence increasing in many countries, especially in children
  
  • 1 in 6 children, 1 in 9 adults
• a major cause of school/work absence
• important condition from a public health perspective

Question 9

What are factors that exacerbate asthma?

Answer 9

• allergens (#1)
• respiratory infections (#3, particularly viral)
• exercise and hyperventilation
• weather changes
• pollutants (sulfur dioxide, occupational fumes) (#2, smoking, still seen in some people who have asthma)
• food, additives, drugs
• emotion

Question 10

How do we make a diagnosis of asthma?

Answer 10

• appropriate clinical setting
• need to demonstrate reversible airflow obstruction (difficult to prove in the setting of an acute exacerbation)
  
  • peak flow
  • spirometry
    
    • ratio of FEV1 to FVC less than 0.7 is highly consistent with asthma
  • airway obstruction that improves using bronchodilater therapy → will see signficant improvement in FEV ratio
• bronchoprovocation test
  
  • measures airway hyperreactivity (AHR)
  • direct (methacholine, histamine) or indirect (exercise, mannitol, hypertonic saline)
  • used on people who have intermittent/variable asthma e.g. exercise induced
• generally want symptoms to be recurrent or variable as opposed to persistent (less likely to be asthma)
• respiratory function report
  
  • first look at FVC → normal range
  • FEV1/FVC % → less than 0.70
  • FEV1 → reduced
  • significant scolloping of respiratory limb ?
  • long tail of expiration commonly seen in patients with airflow obstruction (would expect to see a respiratory limb that takes a much straighter trajectory with exhalation)
  • patient undergoes bronchodilator treatment → significant improvement in FEV1 (to within normal range is what we would hope and expect to see in asthma)
  • significant improvement in FVC → representing relief of gas trapping → small amount of gas trapped at the end of each breath, inhaled but not fully exhaled
  • FVC doesn’t actually change much, it is the residual volume that reduces
  • relief of airway obstruction has relieved some of the dynamic hyperinflation and therefore the measured FVC improves

Question 11

What is the common view and treatment of asthma?

Answer 11

• inflammation (preventer therapy e.g. glucocorticoids) → more important to target
  
  • airway smooth muscle (reliever therapy e.g. B2-adrenoceptor agonists) → doesn’t help and can be a hindrance in the longer term
  • airway hyperresponsiveness (AHR)
    
    • symptoms (avoid triggers)
• remember that asthma treatment is more than just pharmacotherapy (although this is very important)

Question 12

How does asthma medication try to minimise the underlying pathophysiology?

Answer 12

• beta 2 agonists (symptom relievers)
  
  • long and short acting
  • relax smooth muscle, improve airway patency
• inhaled corticosteroids (ICS, preventer)
  
  • reduce airway inflammation and AHR
  • mainstay of asthma treatment in general
• oral corticosteroids (usually only at times of exacerbation)
• combines inhalers (ICS, LABA)
• leukotriene receptor antagonists
• anti-IgE

Question 13

What is the dose-response curve for inhaled corticosteroids?

Answer 13

• daily dose of inhaled steroid (FP ug) vs clinical effect
• only need a modest amount of steroids to produce very good airway control of inflammation
• dosing for asthma significantly reduced compared with COPD
• 100/200mg bd = standard dose = 90% max
• people prescribed 500mg don’t have much increased clinical benefit especially when compared with the adverse effects
• if people are still symptomatic at low doses → combination therapy e.g. long acting beta agonists

Question 14

What is the main focus of asthma control?

Answer 14

• impairment - quality of life
• remodelling and progression
  
  • decline in lung function
  • increase in BHR
  • airway inflammation
• while less significant (cf death) due to the prevalence of asthma this is where the largest societal burden occurs
• days with poor control
• puffs of rescue
• no nights of awakening
• control of the two largest sections of the pyramid → reduce more significant adverse outcomes
• moderate exacerbations
• severe exacerbation
• death
  
  • significant and potential outcome before the use of corticosteroids
  • now a much smaller issue

Question 15

What is COPD?

Answer 15

• group of disorders characterised by airway inflammation and airflow limitation that is not fully reversible
• heterogeneous phenotype of airway obstruction
• broadly speaking divided into two different conditions:
  
  • emphysema: loss of airway tissue
  • chronic bronchitis: chronic airway inflammation and sputum production
  • patients will have a variable amount of those two components of COPD → very different clinical presentations
• a progressive condition associated with an abnormal inflammatory response to noxious stimuli → almost always cigarette smoking
• fully reversible asthma is not COPD

Question 16

What are features of COPD in australia?

Answer 16

• third leading cause of disease burden in Australia (after heart disease and stroke)
• tends to affect people in the older decades of life
• fourth leading cause of death in Australian men and 6th in women
• nearly 500,000 people in Australia with moderate to severe COPD
• mortality from COPD 10-times higher in indigenous Australians
• among prinicipal causes of death, only COPD continues to have a growing death rate

Question 17

What is the only major cause of death that has increased significantly in recent years?

Answer 17

• COPD
• • 163%
• (coronary heart disease, -59%, stroke -64%, other CVD -35%, all other causes -7%)

Question 18

How well is COPD diagnosed?

Answer 18

• COPD is currently:
  
  • under-recognised
  • under-diagnosed
  • under-treated
• COPD is under-diagnosed not only in its early stages but even when lung function is severely impaired
• COPD is a preventable and treatable disease but is still not fully understood by most healthcare providers

Question 19

What is the relationship between smoking and COPD?

Answer 19

• smoking is:
  
  • a major risk factor for developing COPD
  • responsible for 80-90% of COPD cases (on a global scale, in the developed world probably about 95%)
  • up to 50% of long-term smokers develop COPD
  • up to 15 - 12% develop severe airflow limitation
• some studies indicate that women are mores susceptible to the effect of tabacco smoke than men

Question 20

What is the pathogenesis of COPD?

Answer 20

• noxious agent
• inflammation
  
  • small airway disease → airway inflammation, remodelling
  • parenchymal destruction → loss of alveolar attachments, loss of elastic recoil
• airflow limitation

Question 21

What happens to the lung in emphysema?

Answer 21

• small airway disease, mucus
• part of the role of lung tissue is to provide elastic recoil for the airways → holds them open
• small airways don’t have cartilage or anything to keep them open
• when you lose that tissue you lose the elastic recoil
• not as much lung structure keeping the airways open → airways collapse shut

Question 22

What are differences in inflammation and its consequences between asthma and COPD?

Answer 22

• end result for both conditions is airflow limitation
• asthma is a much more acute inflammatory response
  
  • immune cell driven
  • exert their effects only as long as they are triggered
  • reversible phenomenon
• COPD is generally caused by cigarette smoking
  
  • chronic injury to respiratory epithelium and resident alveolar macrophages
  • a lot of that inflammation then becomes self-sustaining which is why patients very frequently remain symptomatic even if they are able to quit smoking
  • irreversible destruction of alveolar tissue
  • persistent small airway obstruction

Question 23

What are the ‘multicomponents’ of COPD?

Answer 23

• inflammation at its core leading to mortality
• mucociliary dysfunction
• structural changes
• airway inflammation
• systemic component
• airflow limitation
• lead to:
  
  • declining lung function
  • symptoms
  • exacerbations
  • decreased exercise tolerance
  • deteriorating health status and increasing morbidity
• now recognised to be a systemic inflammatory disease
• greater degree of systemic involvement equates to poorer prognosis

Question 24

What is the burden of exacerbation?

Answer 24

• reduced quality of life
  
  • physical and mental well being
• accelerated decline in lung function
• 40,000 hospital “separations” each year
• managed with oral corticosteroids
• sometimes antibiotics if patients have suggestions of signifcant bacterial burden
• patients with more frequent exacerbations are known to have a much worse clinical prognosis both in terms of ongoing deterioration in lung function and in likelihood of death in the next 12-24 months

Question 25

What is the aetiology of exacerbations?

Answer 25

• bacteria, virus and air pollution
• around one third of patients with COPD grow bacteria from respiratory specimen during stable state
• trials of antibiotic effectiveness have shown inconsistent results

Question 26

How is COPD diagnosed?

Answer 26

• consider COPD in…
  
  • any past or current smoker
  • chronic cough
  • productive cough
  • dyspnoea
  • history of exposure to other risk factors
  • frequent significant chest infections
  • reduction in exercise tolerance

Question 27

What are other risk factors of COPD?

Answer 27

• recreational drugs: marijuana (particularly bong smoking)
• occupational exposure to irritants
• alpha-1 antitrypsin deficiency → autosomal recessive disorder
• bronchial hyper-responsiveness
• passive smoking
• recurrent RTIs in childhood
• genetic predisposition

Question 28

What is the importance of smoking cessation?

Answer 28

• smoking cessation is the single most effective way to reduce the risk of developing COPD
• slows the accelerated decline in lung function seen in COPD
• reduces mortality due to lung cancer, cardiovascular disease and other comorbid conditions associated with COPD
• from the age of 25 onwards everyone loses a small amount of lung capacity each year (30 to 50mL / year)
• most people who have never smoked or are not susceptible to smoke will never reach the point of disability or death in regards to FEV1 value
• smokers will have double or even triple the decline in lung function per year → likely to get to a point where they develop symptoms based on their FEV1
• if you stop people smoking the trajectory of their lung decline returns to that of a non-smoker
• at any point there is value to stopping smoking → if you can get them to stop before 50 the likelihood of them having a respiratory something is cut by about 90%

Question 29

What are smoking cessation strategies?

Answer 29

• non-pharmacologic
  
  • willpower alone
  • doctor’s advice
  • self-help materials
  • intensive counselling
  • smoking cessation courses
• pharmacologic
  
  • nicotine replacement therapy
  • bupropion (Zyban)
  • varenicline (Champix)
    
    • partial agonists of the nicotine receptor

Question 30

What are Beta-2 agonists?

Answer 30

• short-acting for prn use (symptomatic treatment)
• long acting for regular use
  
  • less symptoms, more exercise, better QOL
• lower QOL with higher doses
• side effects = tremor, tachycardia

Question 31

What are anticholinergics?

Answer 31

• long-acting more convenient
  
  • regular use short acting a/w increased cardiac events
• demonstrated to achieve:
  
  • less dyspnoea
  • better exercise tolerance
  • less exacerbations (NNT = 14)
  • less mortality
• side effect = dry mouth in 14%

Question 32

Are inhaled corticosteroids affective in COPD?

Answer 32

• neutrophilic inflammation-steroid “resistant”
• higher doses than in asthma
• studies show benefit in severe COPD (FEV1 less than 50%) with frequent exacerbations
• risk of pneumonia slightly increased

Question 33

What is the combination therapy used to treat COPD?

Answer 33

• inhaled fluticasone and salmeterol (seretide)
• inhaled budesonide and formoterol (symbicort)
• in moderate to severe COPD (FEV1 less than 60%) may
  
  • reduce exacerbations
  • improve QOL
  • improve FEV1
• however fallen out of favour mostly

Question 34

What are other strategies for treating COPD?

Answer 34

• theophyllin (reduces sense of dyspnea), roflumilast (phosphodiesterase inhibitor, can reduce airway inflammation/exacerbations, but expensive w/ limited evidence)
• long term antibiotics
  
  • there may be a role for macrolides
• pulmonary rehabilitation
  
  • very important
  • particularly in patients with fixed exercise intolerance
• vaccinations
  
  • significant mortality benefit in receiving flu vaccine
  • pneumococcal vaccine also recommended but limited evidence to support its use
• oxygen
  
  • only for very severe patients with hypoxia (resting oxygen content of less than 55mL/Hg)
• lung volume reduction → not generally performed
  
  • surgical
  • bronchoscopic
    
    • valves
    • steam

Question 35

conclusion

Answer 35

• conditions that result in airflow limitation are common
• they have significant morbidity and mortality
• treatments can control airway inflammation in asthma but are less efficacious in COPD
• novel therapies are required to improve patients with permanent airflow limitation