asthma and copd

Question 1

What are the key definitions of COPD and asthma?

Answer 1

1. Both asthma and COPD are chronic inflammatory diseases of the respiratory tract resulting in airway obstruction and a failure of normal alveolar ventilation and gaseous exchange.
2. However, asthma is characterized by variable and reversible obstruction which is rarely progressive.
3. COPD encompasses co-occurrence of chronic bronchitis and emphysema which involves persistent obstruction which is normally irreversible and progressive. Thus, the pathophysiology, clinical presentation and treatment of these two diseases are in some respects distinct.

Question 2

Where is inflammation in asthma?

Answer 2

1. Inflammation is present in the small (<2mm) and large (>2mm) airways of the lung in asthma, even in the stable state.
2. Carroll et al (1997) performed histological examination and reported increased levels of neutrophils and eosinophils in both the large and small airways of subjects with fatal and non-fatal asthma, compared to controls.
3. Large airway inflammation is typically characterised by CD4+ Th2 cells and mast cells, whilst eosinophilia defines the smaller airways. There is debate in the literature as to the relative importance of these two compartments.
4. Hamid et al (1997) reported that inflammation of the peripheral airways is more important, due to constriction, thickening and eosinophil infiltration of these airways. In contrast
5. Poulter et al (1997) reported that inflammation of the large airways, and Th2 cells accumulation here, is of greater pathophysiological importance.

Question 3

Where is inflammation in COPD?

Answer 3

1. Inflammation in COPD is largely in the small airways. It is characterised by CD8+ T cells, macrophages and neutrophils.
2. However, there is some evidence to support that there is CD8+ cell infiltration of the large airways, and large airway inflammation becomes important in chronic bronchitis.
3. Eosinophils may be present in exacerbated COPD.

Question 4

What is the nature of obstruction in asthma?

Answer 4

1. Airway smooth muscle cell hypertrophy allows for excessive bronchoconstriction in asthma. This bronchoconstriction is due to hyper-responsiveness to a number of stimuli – including pollution, cigarette smoke and allergens.
2. Bronchoconstriction usually results from mast cell activation and degranulation, releasing histamine.
3. In severe and fatal asthma, bronchoconstriction is compounded by oedema of the respiratory epithelium and mucus plugging.

Question 5

What is the nature of obstruction in COPD?

Answer 5

1. Nearly all cases of COPD are associated with smoking which can act to upregulate activity of proteases, down-regulate the effects of anti-proteinases, and increase pulmonary structural cell apoptosis.
2. The result is destruction of the structural parenchymal alveolar attachments which help to keep airways open during expiration. Loss of these attachments allows alveolar collapse and atelectasis during expiration.
3. In emphysematous COPD there is destruction of the alveolar septa allowing formation of large, dilated air sacks known as emphysematous bullae. These can be visualised on a chest radiograph, and are usually hyperinflated, leading to flattening of the hemidiaphragm.
4. Bullae compress normal alveoli, restricting their ventilation. Bullae formation also considerably reduces the surface area for gaseous exchange, and fibrosis of the alveolar epithelium leads to thickening of the diffusion barrier.
5. Acute exacerbations of COPD can result in alveolar oedema.
6. Chronic bronchitis in COPD can lead excessive mucus production by the airways, contributing to increased airway resistance. A combination of reduced ventilation, atelectasis, reduced surface area, and diffusion limitation contribute to hypoxaemia which can be seen in some COPD.

Question 6

What is the peak expiratory flow rate?

Answer 6

PEFR is measured using a dry rolling-seal spirometer, pneumotachograph or turbine – i.e. equipment with a high frequency response. Measures of flow can be integrated to give measure of volume.

Question 7

What is the PEFR in asthma?

Answer 7

Asthma presents as variable, diurnal reduction in PEFR. Diurnal variation can be reduced, and peak flow increased, via administration of a bronchodilator.

Asthma: ↓PEFR, ↓flow at beginning of expiration, straight line

Question 8

What is the PEFR in COPD?

Answer 8

COPD presents as fixed reduction in PEFR with no diurnal variation

COPD: ↓↓PEFR, concave line, low exp flow throughout, flow less than that at rest

Question 9

What are FVC and FEV1?

Answer 9

1. FVC is the volume of air which can be forcibly expired from the lungs after maximal inspiration.
2. FEV1 is the volume of air which can be forcibly expired in 1 second.

Question 10

How do FVC and FEV1 change in asthma and COPD?

Answer 10

1. Being obstructive lung diseases, both forced vital capacity and FEV1 are reduced in asthma and COPD. Furthermore the FEV1/FVC ratio is less than 70%.
2. FEV1 as a percentage of predicted values (for age, gender and weight) can be used as a measure of severity of these diseases.
3. The National Heart, Lung and Blood institute grade severe asthma as an FEV1 < 60% predicted.
4. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines very severe COPD as FEV1 < 30% predicted.
5. FEV1 is a strong predictor of mortality in COPD and is one of the categories in the BODE index used to determine the severity of COPD. The BODE grading is better than FEV1 at predicting mortality from COPD.

Question 11

How does FEV1 change over time in COPD and asthma?

Answer 11

1. Fletcher & Peto (1977) performed a seminal prospective epidemiological study in London working men, in which they monitored FEV1 progression.
2. There was a natural decline in FEV1 with age, even in healthy subjects.
3. However, in smokers with COPD the rate of FEV1 decline was much increased. If a COPD patient quits smoking, lung function does not return to normal, but the rate of FEV1 decline is reduced.
4. Similar, although less dramatic, decline in FEV1 is seen in individuals with asthma over time.

Question 12

What is broncho-dilator reversibility?

Answer 12

1. Bronchodilator reversibility (BR) is characterized as an increase in FEV1 of >20% or >200mls in response to a specific does of a β2-agonist bronchodilator.
2. Asthma is classically responsive to bronchodilators, but the absence of BR does not preclude a diagnosis of asthma.
3. COPD is considered to be unresponsive to bronchodilators. However, the UPLIFT study demonstrated that 50% of COPD is responsive to the anticholinergic vasodilator tiotropium, and that bronchodilator administration can reduce the mortality from COPD and slow progressive loss of lung function.
4. However, the degree of BR in COPD is not reflective of prognosis.

Question 13

What is hyper-responsiveness?

Answer 13

1. It is hyper-responsiveness of the airways in asthma which induces excessive bronchoconstriction and airway obstruction. Thus, asthma characteristically responds to a pharmacological bronchoconstrictor challenge (often histamine) with a transient reduction in FEV1.
2. This response is largely absent from COPD patients. Asthma patients will often show atopic response in skin prick tests. Defined by use of methacholine or histamine concentration needed to provoke a 20% reduction in FEV1 – healthy non-asthmatics require several magnitude higher concentrations.

Question 14

What happens to the lung volumes in COPD and asthma?

Answer 14

1. COPD and the formation of emphysematous bullae is associated with lung hyperinflation and thus and increase in TLC but a decrease in inspiratory capacity as determined by spirometry and helium dilution techniques (to measure RV).
2. Airway collapse and atelectasis results in trapping of gas behind closed airways, leading to an increase in residual volume. This is associated with a concomitant reduction in vital capacity.
3. O’Donnell et al (2004) performed a double-blind randomized control trial and demonstrated that inspiratory capacity is a good indicator of air trapping and predicting exercise capacity in COPD. Similar changes in lung volume can be seen in individuals with persistent asthma and are accompanied by increased airway resistance.

Question 15

How do arterial blood gases change in asthma and COPD?

Answer 15

1. Stable asthma is associated with normoxia and normocapnia.
2. However, acute exacerbations of asthma can be associated with hypoxaemia with or without hypercapnia.
3. Similarly, COPD can be associated with normal blood gasses, or hypoxaemia +/- hypercapnia

Question 16

What is the treatment of COPD based on?

Answer 16

1. GOLD guidelines, now based on exacerbation history and symptoms rather than FEV1, for the treatment of COPD involve administration of short acting bronchodilators (β2-agonists like salbutamol, or anticholinergics like ipratropium) for symptomatic relief, alongside long acting bronchodilators (tiotropium) and inhaled glucocorticoids.
2. Glucocorticoids don’t provide immediate symptomatic relief but reduce inflammation.
3. This should be coupled with a reduction of risk factors for acute exacerbation and progression, such as influenza vaccination and smoking cessation.
4. The National Emphysema Treatment Trial (2003) reported a 40% reduction in mortality in patients with upper lobe emphysema after lung volume reduction surgery.
5. This is because removal of bullae allows re-expansion of normal lung tissue. However, the benefit of this surgery is restricted to a specific subset of individuals with COPD.
6. Long term oxygen therapy is a potential treatment, but its benefit is contentious. Timms et al (1985) reported improved haemodynamic in COPD patients with severe hypoxaemia with LTOT of more than 15 hours a day, which was associated with better survival. However, many studies refute its clinical benefit.

Question 17

What are the treatment guidelines for asthma?

Answer 17

1. Since asthma is variable (diurnal / seasonal) treatment should aim to improve the ‘level of control’ of asthma and should evolve and adapt with the dynamic nature of the individual’s disease.
2. It is treated in a step-wise manner
3. Prevention is key – so stimuli such as allergens, cigarette smoke and pollution should be avoided.
4. Fast-acting bronchodilators can improve symptoms.

5 .Longer-term control is achieved by long-acting β2-agonists (salmeterol), leukotriene antagonists, and inhaled glucocorticoids.

6. Uncontrolled asthma may be treated with oral glucocorticoids and anti-IgE treatment.

Question 18

What is the overlap of asthma and COPD?

Answer 18

1. This essay has presented asthma and COPD as distinct diseases.
2. Kim et al (2010) review evidence suggesting that asthma can present with fixed obstruction and CD8+ cell accumulation, whilst COPD may show hyper-responsiveness and eosinophilia. As such there is blurring of the distinctions between these pathologies.
3. Seriano et al (2003) reported that 19% of individuals with obstructive lung disease in the UK have symptoms of asthma, chronic bronchitis and emphysema – sometime referred to as ‘wheezy bronchitis’

Question 19

What are the reasons for the increasing prevalence of asthma?

Answer 19

1. Approximately 300 million people have asthma worldwide, and its prevalence increases by 50% every decade.
2. This is a dramatic increase in prevalence, but the underlying reasons remain unclear.
3. It may, in part, be due to a widening of the diagnostic inclusion criteria, such that more people are classified as ‘asthmatic’. Increased asthma prevalence has also been associated with increases in other diseases of ectopic sensitization, such as eczema and rhinitis, and may result from increased levels of allergenic stimuli like pollution and cigarette smoke.
4. However, Seaton et al (1994) pose that increased asthma is not due to increased environmental toxicity, but instead increased individual sensitivity.
5. Reduced fruit and vegetable consumption as part of a western diet is associated with reduced antioxidants in the body and reduced protection against oxidant stress. Reactive oxygen species can damage the respiratory mucosa, allowing allergens to stimulate mast cell degranulation.
6. Black & Sharp (1997) proposed the lipid hypothesis. Increased consumption of omega-6 polyunsaturated fatty acids results in alteration of cell membranes, increasing the amount of arachidonic acid, which is used to synthesise PGE2. PGE2 can promote phenotypic switch of Th cells to Th2, which allow class switching of Abs to IgE which sensitise mast cells to allergens.
7. It is becoming increasingly recognised that ectopic sensitisation to allergens begins in utero. Thus, maternal nutrition can be implicated. Reduced maternal consumption of vitamin E results in increased Th2 cell compartments, and thus increased sensitisation to allergens.
8. Furthermore, reduced vitamin E consumption can disrupt normal foetal lung development.

Question 20

Why do we need to diagnose/treat small airway disease?

Answer 20

As we have discussed, there is some ambiguity in distinguishing COPD from asthma in conventional lung function tests – both result in reduced PERF and reduced FEV1. Furthermore, it is becoming increasingly recognised that COPD can show BR and some degree of hyper-responsiveness. In 1967 used retrograde movement of a 2mm bell-end catheter to define small airways as those smaller than 2mm diameter. These small airways contribute to only 10% of total lung resistance, and as such there can be extensive small airway disease before there are changes in conventional lung function tests.

Question 21

What did Greene (1998) do?

Answer 21

Greene (1998) reviewed the limitations of current lung function tests for determination of small airway disease, and highlight the potential of high resolution CT scanning (HRCT). HRCT can image the small airways, and often reveals ‘mosaic perfusion’ in lung disease due to reflex vasoconstriction of vessels supplying hypoxic alveoli.

Question 22

What did Paredi et al (2010) do?

Answer 22

Paredi et al (2010) propose a novel means of assessing small airway function through use of forced oscillometry at 5Hz. This can be used to assess intrabreath differences in inspiratory-expiratory reactance. Large differences in reactance are suggestive of expiratory flow limitation. Subjects with COPD have large differences in intra-breath reactance, whilst those with asthma do not. Thus this is a potential diagnostic aid in differentiating asthma from COPD.

Question 23

What did Berry et al (2005) do?

Answer 23

Berry et al (2005) were able to demonstrate a correlation between exhaled alveolar nitric oxide (NO) and the degree of eosinophil infiltration of the airways in asthma (as determined by bronchioalveolar lavage). Furthermore, exhaled alveolar NO was increased in individuals with refractory asthma. Thus, in may provide an additional test of lung function. NO is increased with severity of asthma as it is produced by inducible nitric oxide synthase (iNOS) which is upregulated in response to atopic stimuli like cigarette smoke, and in response to inflammatory cytokines.

Question 24

How can ventilation homogeneity be measured?

Answer 24

1. Ventilation inhomogeneity in the lungs can be measured by used of multiple breath nitrogen washout tests.
2. Ventilation inhomogeneity can be differentiated into that arising at the level of the alveoli, and that at the level of the conducting airways. Asthma has been shown to have increased acinar ventilation inhomogeneity, but this is much worse in COPD.
3. Conductive airway inhomogeneity is affected to a similar degree in COPD and asthma. Furthermore, heterogeneity is reduced in response to bronchodilators in asthma, but not COPD.
4. Nitrogen washout tests are then another means of differentiating COPD and asthma.

Question 25

What is HP?

Answer 25

Inhaled hyperpolarised helium (HP) can be visualised by MRI. In healthy subjects, the HP is seen to quickly distribute evenly throughout the lungs. In lung disease, distribution is much slower, and there are multiple defects. Thus, HP inhalation can give an indication of the degree and severity of small airway disease.

Question 26

Why is it important to target small airway diseases?

Answer 26

It is important to target the small airways, Usmani et al 2015 found that treating peripheral airways with small drug particle aerosols achieves comparable (and in some studies superiority) in efficacy compared with large particles. It enables greater control of asthma in real life. And it allows a reduction in the daily inhaled corticosteroid dose.

Question 27

What are small airways?

Answer 27

• Small airways contribute only 10% of airway resistance
• Extensive disease can be present in the small airways without changes in lung function tests (e.g. spirometry)
• ∆ small airways sometimes referred to as the ‘silent zone’ of the lung.

Question 28

What did Macklem and Mead do?

Answer 28

• Macklem & Mead (1967)
o Defined large and small airways as >2mm / <2mm
o Whether a 2mm bell-end catheter could be moved retrogradely through the airway

Question 29

Who recognised that there is a need for tools to identify small airway disease?

Answer 29

o Recognition of inadequacies of current lung function tests & investigations in determining small airway disease.
o High resolution computed tomographic (HRCT) scanning captures fine lung detail that can demonstrate morphological changes in the small airways associated with dysfunction too subtle to be identified on lung function testing alone.
o The HRCT appearance of small airways disease shows “mosaic perfusion”—thought to be a consequence of reflex vasoconstriction in underventilated areas of the lung.

Question 30

What is forced oscillometry?

Answer 30

Paredi et al 2010
o Use of 5Hz forced oscillometry to measure respiratory reactance within-breath – i.e. inspiratory-expiratory breath analysis.
o Large inspiratory-expiratory variations in reactance at 5 Hz is a marker of expiratory flow limitation
o People with COPD have large inspiratory-expiratory variation in reactance
o In contrast, no significant difference in asthma.

Question 31

What is exhaled NO?

Answer 31

Berry et al (2005)
o Exhaled NO correlates with eosinophils in BAL
o Exhaled NO ↑ in refractory asthma
o ‘Refractory’ = difficult to control

Question 32

What is ventilation inhomogeneity?

Answer 32

Ventilation inhomogeneity can differentiate between asthma & COPD
• Can use multiple breath N2 washout whilst breathing 100% O2 to determine ventilation imhomogeneity in the conductive (Scond) and acinar (Sacin) airways separately.
o Acinar ventilation inhomogeneity was abnormal in patients with asthma, but it was considerably worse in patients with COPD
o Conductive ventilation inhomogeneity was abnormal to a similar degree in COPD and asthma.
o Measurements after salbutamol inhalations showed significant changes in S(cond) and S(acin) only in the patients with asthma

Question 33

What is dynamic HP helium and MRI?

Answer 33

o High speed recording to visualise hyperpolarised helium as it is inspired
o In healthy volunteer it distributes rapidly and evenly
o In patient with emphysema and severe airway disruption, the lungs fill slower and with multiple defects.